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The Biology of NKT Cells
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Albert Bendelac,1 Paul B. Savage,2
and Luc Teyton3
1
Howard Hughes Medical Institute, Committee on Immunology and Department of
Pathology University of Chicago, Chicago, Illinois 60637;
email: [email protected]
2
Department of Chemistry, Brigham Young University, Provo, Utah 84602;
email: paul [email protected]
3
Department of Immunology, Scripps Research Institute, La Jolla, California 92037;
email: [email protected]
Annu. Rev. Immunol. 2007. 25:297–336
Key Words
First published online as a Review in
Advance on December 6, 2006
natural killer T cell, lymphocyte development, innate immunity,
α-proteobacteria, Sphingomonas, Ehrlichia, Salmonella, glycolipid,
CD1d, antigen presentation
The Annual Review of Immunology is online
at immunol.annualreviews.org
This article’s doi:
10.1146/annurev.immunol.25.022106.141711
c 2007 by Annual Reviews.
Copyright All rights reserved
0732-0582/07/0423-0297$20.00
Abstract
Recognized more than a decade ago, NKT cells differentiate from
mainstream thymic precursors through instructive signals emanating during TCR engagement by CD1d-expressing cortical thymocytes. Their semi-invariant αβ TCRs recognize isoglobotrihexosylceramide, a mammalian glycosphingolipid, as well as microbial
α-glycuronylceramides found in the cell wall of Gram-negative,
lipopolysaccharide-negative bacteria. This dual recognition of self
and microbial ligands underlies innate-like antimicrobial functions
mediated by CD40L induction and massive Th1 and Th2 cytokine
and chemokine release. Through reciprocal activation of NKT cells
and dendritic cells, synthetic NKT ligands constitute promising new
vaccine adjuvants. NKT cells also regulate a range of immunopathological conditions, but the mechanisms and the ligands involved
remain unknown. NKT cell biology has emerged as a new field
of research at the frontier between innate and adaptive immunity,
providing a powerful model to study fundamental aspects of the
cell and structural biology of glycolipid trafficking, processing, and
recognition.
297
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INTRODUCTION
Natural killer T
(NKT) cell: a T cell
expressing a
CD1d-restricted,
lipid-specific T cell
receptor combining
a canonical
Vα14-Jα18 α chain
with a variable Vβ8,
-7, or -2 β chain in
mouse or
Vα24-Jα18/Vβ11 in
human
CD1: a family of
MHC-like molecules
that specialize in
presenting lipid
antigens to
T lymphocytes
α-glycuronylceramides:
glycolipids that
substitute for LPS in
the cell wall of
Gram-negative,
LPS-negative
bacteria such as
Sphingomonas
298
Several lines of research led to the identification of NKT cells as a separate lineage of
T lymphocytes. The first sightings included
(a) the identification of a canonical Vα14Jα18 ( Jα18 was previously known as Jα281 or
Jα15) rearrangement in a set of hybridomas
derived from mouse KLH (keyhole limpet
hemocyanin)-specific suppressor T cells
(1–3), and later in cDNA extracted from lymphoid organs of unimmunized mice (4, 5);
(b) the identification of a subset of mouse
CD4− 8− double-negative (DN) T cells with
a Vβ8 usage bias (6, 7); and (c) the identification of a recurrent Vα24-Jα18 rearrangement in human DN peripheral blood lymphocytes (8, 9). These observations were pieced
together when a subset of CD4 and DN
IL-4-producing thymocytes co-expressing
NK lineage receptors was independently
identified and shown to express a biased set
of Vβ8, Vβ7, and Vβ2 T cell receptor (TCR)
β chains (10–13) combined with a canonical
Vα14-Jα18 in mouse (14) and with the homologous Vα24-Jα18/Vβ11 pair in human
(14, 15). The finding that the mouse and human NKT cells were autoreactive to cells
expressing CD1d (15–18), a member of the
CD1 family of MHC-like molecules, completed the initial characterization of this lineage and raised modern questions relating to
their development, specificity, and function.
These issues have been treated in more
than 1500 reports over the past 10 years, more
than 300 of which were published in the past
year alone. We attempt to organize a critical
understanding of the general biology of NKT
cells, mainly of the predominant mVα14 and
hVα24 subsets, on the basis of recent fundamental advances and newly emerging concepts. Owing to space limitations, it is not possible to exhaustively review or mention all the
studies, many of which suggest new roles of
NKT cells in various diseases and remain relatively preliminary or isolated. We focus on
bacterial infections where the role of NKT
cells is well established and examine a selec-
Bendelac
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Teyton
tion of autoimmune, allergic, and tumor conditions of broad clinical interest, where the
function of NKT cells remains speculative or
controversial.
DEFINITION
NKT cells are narrowly defined as a T cell
lineage expressing NK lineage receptors, including NK1.1 in the C57BL/6 background,
in addition to semi-invariant CD1d-restricted
αβ TCRs. More than 80% of these TCRs
are Vα14-Jα18/Vβ8, Vβ7, and Vβ2 in mouse
(or Vα24-Jα18/Vβ11 in human), with the
remaining representing a collection of rare
but recurrent Vα3.2-Jα9/Vβ8, Vα8/Vβ8,
and other TCRs (19, 20). Whereas both
the Vα14 and the non-Vα14 NKT cells
exhibit autoreactivity to CD1d-expressing
cells, particularly thymocytes, their antigen
specificities do not overlap. Thus, mVα14
and hVα24 NKT cells, irrespective of their
Vβ-Dβ-Jβ chain usage, recognize a marine sponge–derived α-galactosylceramide
(αGalCer) (21, 22) and closely related microbial α-glycuronylceramides (23–25), as well
as the self antigen isoglobotrihexosylceramide
(iGb3) (26). In contrast, the self and foreign
antigens recognized by non-Vα14 NKT cells
remain to be identified. A striking, generic difference between Vα14 and non-Vα14 NKT
cells is that the natural Vα14 NKT ligands,
including iGb3, require endosomal trafficking of CD1d and intact lysosomal functions
for presentation at the cell surface, whereas
the non-Vα14 ligands are normally presented
by a tail-truncated CD1d, which is defective
in endosomal trafficking and likely presents
antigens loaded in the secretory pathway or at
the cell surface (27). These CD1d-restricted
NKT cells should be distinguished from
CD1d-restricted T cells that express noninvariant TCRs and from a variety of other nonCD1d-restricted T cells that express NK lineage receptors (28, 29). Although some studies
have recently implicated non-Vα14 CD1drestricted T cells in various diseases, this
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review focuses mainly on the canonical
mVα14 and hVα24 NKT cells.
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SPECIES AND TISSUE
DISTRIBUTION
Vα14 NKT cells have been well characterized
in mouse, where they represent ∼0.5% of the
T cell population in the blood and peripheral
lymph nodes, ∼2.5% of T cells in the spleen,
mesenteric, and pancreatic lymph nodes, and
up to 30% of T cells in the liver. Although
their precise distribution within the lymphoid
organs is still unknown, they reside within the
liver sinusoids, which they appear to patrol.
Their expression of CXCR6 matches the expression of CXCL16 on the endothelial cells
lining the sinusoids and appears to be important for survival rather than for migration (30).
NKT cell frequency in the whole thymus is
∼0.5%, but they represent up to 5% of the
recent thymic emigrants found in the spleen
(31, 32). Although the tissue distribution is
less well studied in humans, Vα24 NKT cells
appear to be ∼10 times less frequent in all
these locations. However, high and low NKT
cell expressors exist in mice and in humans,
and NKT cell frequency appears to be a stable phenotype under the genetic control of
at least two recessive loci in mouse (33, 34).
Low Vα14 NKT cell expressors in mice include NOD and SJL (35–37). The range of
frequencies found in human blood varies by
up to 100-fold between individuals but is under strict genetic control, as shown by identical twin studies (38). Similar frequencies have
been found in nonhuman primates (39). Vα14
NKT cells are present in rats (40, 41), and,
based on genomic and functional studies of
CD1d, they may be absent in cows (42).
NKT LIGANDS
Although disputed initially (43), there is now
a general consensus that CD1d, like other
CD1 family members, evolved to present
lipids to T cells (44). However, the nature
and the source of the various lipids that
bind naturally to CD1d remain poorly elucidated. Early studies of CD1d immunoprecipitates obtained from cell detergent lysates
suggested a predominance of phospholipids—
particularly glycosylphosphatidylinositols, an
anchor for various surface proteins, and phosphatidylinositols (45, 46). However, because
these early studies used detergents that could
potentially displace natural lipids bound to
CD1d, or soluble forms of CD1d that did
not traffic through the endosome and might
have acquired irrelevant lipids from membrane compartments or culture medium, their
interpretation is uncertain. Future studies of
CD1d molecules engineered to express an
enzymatic cleavage site at the membraneproximal portion of their extracellular domain
constitute an attractive approach to reexamining this fundamental issue. Despite a lack
of direct biochemical studies of CD1-bound
lipids, combinations of genetic, cell biological,
and chemical approaches have nevertheless
uncovered some key NKT ligands discussed
below.
Marine Sponge αGalCer
The first NKT ligand emerged from studies
initiated at Kirin Pharmaceuticals to identify
natural anticancer medicines. Extracts from
Agelas mauritianus, a marine sponge collected
in the Okinawan sea, prolonged survival of
mice bearing B16 melanoma (47). The structure of the active principle was identified as an
α-branched galactosylceramide and slightly
modified for optimal efficacy to produce a
compound termed KRN7000, also commonly
referred to as αGalCer (Figure 1) (48). The
lipid nature of this compound, its strong effect on liver metastasis, and its activation of
dendritic cells (DCs) independent of MHC
class I or class II (49) led to the identification of Vα14 NKT cells as their target
(21). As a surrogate ligand of very high activity in vitro and in vivo, in the picomolar range αGalCer has been used broadly in
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a
OH
αGalCer
(KRN7000)
OH
C6"
12:20
O C2'
C1"
HN
OH
OH
C3
O
C2 C4
OH
HO
O
b
O
HOOC
HO
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GSL-1
O
HO
OH
HN
OH
O
OH
HO
HO
HO
O
NH2 HOOC
O
GSL- 2
HO
HO
HO
HO
O
O
HN
OH
O
OH
O
O
OH HO
HO
GSL- 3
OH
O
NH2 HOOC
O
HO
HO
HO
HO
O
HN
O
OH
OH
O
NH2 HOOC
O
O
OH
HO
HO
HO
OH
O
O HO
HO
GSL- 4
O
O
HO
O
O
OH
HN
O
OH
OH
c
OH
iGb3
HO
OH
O
OH
OH
O
OH
O
O
OH
OH
O
HO
O
OH
HN
O
OH
Figure 1
Self and microbial glycosphingolipid ligands (GSL) of NKT cells. (a) Marine sponge αGalCer
(KRN7000) with carbon atom number assignments on sphingosine (C), acyl (C ), and carbohydrate (C );
(b) Sphingomonas GSL-1 through GSL-4; and (c) mammalian isoglobotrihexosylceramide (iGb3), or
Galα1,3Galβ1,4Glcβ1,1Cer. Note that the proximal glucose of the mammalian glycosphingolipid has a
β-anomeric linkage to ceramide, in contrast with the α-branched galactose of αGalCer or glucuronyl of
Sphingomonas GSLs.
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various functional assays and to generate the
first CD1d tetramers specific for mouse and
human NKT cells. The affinity of interaction
between CD1d-αGalCer and mouse TCRs is
one of the highest ever recorded for natural
TCR/ligand pairs with a Kd ∼100 nM, owing
to a slow off rate, for several Vα14-Jα18/Vβ8
combinations examined (50, 51) and may
be significantly lower in the human system
(∼7 μM) (52). Although the expression of this
ligand in marine sponges could not be linked
with any physiologically relevant function, the
striking properties of αGalCer have provided
early support for the hypothesis that the conserved TCRs of NKT cells evolved to recognize conserved lipids. More than 95% of
cloned mouse and human NKT cells recognize αGalCer, irrespective of their variable
CDR3 β sequence, and the mouse CD1dαGalCer tetramers stain human and nonhuman primate NKT cells as well (22, 39), attesting to the high degree of conservation of
this recognition system.
Microbial Ligands
The lack of physiological relevance of
αGalCer should be revisited with the recent discovery that closely related structures that substitute for lipopolysaccharide
(LPS) are found in the cell wall of Sphingomonas, a Gram-negative, LPS-negative
member of the class of α-proteobacteria (53,
54). These glycosphingolipids are responsible for the strong stimulation of NKT cells
and their role in clearing infection (23–25, 55).
The most abundant glycosphingolipids have
only one sugar, galacturonyl or glucuronyl,
α-anomerically branched to the ceramide
backbone (Figure 1, GSL-1). Thus, they differ from the stimulating αGalCer or αGlcCer
mainly by the carboxyl group in C6 , a position permissive to NKT cell recognition
(56, 57). Other more complex but less abundant glycosphingolipids include GSL-2, -3,
and -4 (Figure 1). Because in general it
is known that extracts from A. mauritianus
have different properties depending on sea-
α-PROTEOBACTERIA
α-proteobacteria constitute one of the most ubiquitous classes
of Gram-negative bacteria on Earth. They exhibit a wide
range of lifestyles, from free-living to obligate intracellular
pathogens, and are found in marine and soil environments.
Obligate intracellular organisms include the Rickettsiales, with
lethal tick-borne pathogens such as Rickettsia and Ehrlichia,
agents of the ancient plague epidemic typhus, Rocky Mountain spotted fever, and other severe febrile and typhus-like
syndromes. Whereas some of the Rickettsiae express LPS,
the Ehrlichiae lack the genes required for LPS and peptidoglycan synthesis, and the composition of its cell wall is
mysterious. Mitochondria represent the ultimate example of
α-proteobacteria that have established an obligate relationship with eukaryotic hosts. Bartonella and Brucella (an LPS
expressor) belong to a group phylogenetically related to the
Rickettsiales. Sphingomonas is a ubiquitous bacterium found in
marine (e.g., sponges and corals) and terrestrial environments
that is actively studied by industrial microbiologists because
of its ability to degrade xenobiotic aromatic compounds. Its
cell wall contains α-glycuronylceramide ligands of NKT cells,
instead of LPS. Sphingomonas was detected by PCR in stool
samples of 25% of healthy human beings and can cause acute
infections, particularly in immunocompromised individuals.
Intriguingly, on the basis of the presence of a specific antibody response in patients’ sera, it has been implicated in the
etiopathogeny of primary biliary cirrhosis, a chronic autoimmune disease targeting intrahepatic bile ducts.
son and location and because these sponges
are often colonized by α-proteobacterial symbionts, particularly by Sphingomonas (58), the
marine sponge αGalCer may in fact have originated from bacterial symbionts.
Self Ligand iGb3
Although the discovery of bacterial NKT ligands provides a fascinating new perspective on
the evolutionarily relevant functions of NKT
cells, considerable attention has also focused
on self ligands. Indeed, mouse and human
NKT cells exhibit conspicuous low-level autoreactivity to various CD1d-expressing cell
types (15, 17, 59). This autoreactivity and
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the presence of IL-12, triggered by Tolllike receptor (TLR) signaling, are required
for the commonly observed IFN-γ secretion by NKT cells during immune responses
against Gram-negative, LPS-positive bacteria (23, 60). Autoreactivity may also underlie the thymic development of NKT cells
(18), which includes an expansion phase after positive selection (31) and the acquisition of a memory phenotype independent of
microbial exposure or TLR signaling (61).
Recent findings demonstrate that the glycosphingolipid iGb3 (Figure 1), both natural and synthetic, could activate a majority of
mouse Vα14 and human Vα24 NKT cells,
irrespective of their Vβ chain, upon presentation by DCs or plastic-bound CD1d/iGb3
preformed complexes (26, 62, 63). iGb3 appears to be a weaker agonist than αGalCer,
requiring ∼30- to 100-fold higher concentrations to achieve the same level of stimulation. This may explain the failure to
stain NKT cells using CD1d/iGb3 tetramers.
However, solubility issues and more stringent requirements for professional antigenpresenting cells (APCs) may contribute to its
lower apparent activity, and the affinity of
CD1d/iGb3-TCR interactions remains to be
measured directly, particularly to dissect the
contribution of on and off rates.
Different lines of experiments suggest
that iGb3 is an important physiological
NKT ligand. β-hexosaminidase-B-deficient
mice, which lack the ability to degrade
iGb4 into iGb3 in the lysosome, exhibited
a 95% decrease in thymic NKT cell production, and β-hexosaminidase-B-deficient
thymocytes could not stimulate autoreactive
Vα14 NKT cell hybridomas (26). Notably,
unlike other mutations of enzymes or transporters involved in lipid metabolism and associated with lipid storage, the defect in
β-hexosaminidase-B-deficient cells appeared
to be specific in that β-hexosaminidase-Bdeficient bone marrow–derived DCs normally presented several complex derivatives
of αGalCer that required lysosomal processing prior to NKT cell recognition, but lost
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their ability to process and present iGb4—the
precursor to iGb3—or GalNAcβ1,4GalαCer,
both of which require removal of the outer,
β-branched hexosamine for NKT cell recognition. In addition, the Griffonia simplicifolia
isolectin B4 (IB4) specific for the terminal
Galα1,3Gal blocked CD1d-mediated presentation of both exogenous iGb3 and endogenous ligand (natural autoreactivity), but not
αGalCer. These studies suggest that iGb3 is
an important physiological ligand of NKT
cells. Additional findings reviewed below suggest that iGb3 may also be the natural ligand
activating NKT cells during Gram-negative,
LPS-positive infections. These results are
therefore consistent with the requirement for
endosomal trafficking of CD1d (27, 64) and
the role of lysosomal saposins functioning as
glycosphingolipid exchange proteins in the
presentation of the NKT ligand in vivo (65,
66). It should be noted, however, that the presence of iGb3 among CD1d-bound lipids remains to be demonstrated and that iGb3 itself
has not yet been directly identified in human
or mouse tissue, a task complicated by the rarity of iGb3 and the dominance of the regioisomer Gb3. Furthermore, other than the enzymatic pathways of synthesis and degradation,
little is known about the general biology of
iGb3, its subcellular location, or its function.
Other NKT Ligands
α-galactosyldiacylglycerols expressed by
Gram-negative
LPS-negative
Borrelia
burgdorferi, the agent of Lyme disease,
resemble α-galactosylceramide and could
directly stimulate NKT cells (67). However,
recognition of intact or heat-killed bacteria
could not be demonstrated, and only one isolated report has suggested defective bacterial
clearance in vivo (68).
Purified phosphatidylinositolmannoside
PIM4, a mycobacterial membrane phospholipid, was reported to elicit IFN-γ but not
IL-4 production from a fraction of mouse and
human NKT cells, and PIM4-loaded CD1d
tetramers showed weak staining of a fraction
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of NKT cells (69). However, CD1d-deficient
mice did not reveal defects in mycobacterial
clearance (70), and a synthetic PIM4 failed to
stimulate NKT cells (67). Because multiple
components of the mycobacterial cell wall
are strong activators of TLR expressed
by APCs, contaminating lipids associated
with the PIM4 preparation may cause indirect stimulation of NKT cells through
presentation of their endogenous ligand
and amplification of IFN-γ production by
TLR-induced IL-12 (see Dual Reactivity to
Self and Microbial Ligands: A Paradigm for
NKT Cell Activation and Function During
Bacterial Infections).
Purified phospholipids originally extracted
from tumors, such as phosphatidylinositol, phosphatidylethanolamine, and phosphatidylglycerol, weakly stimulated some
Vα14 and non-Vα14 NKT hybridomas when
loaded onto recombinant CD1d, but there is
little support at present for their physiological importance because neither the tumor nor
the synthetic lipids could expand or activate
fresh NKT cells in vivo or in vitro (71). Another report suggested the presence of CD1drestricted phosphatidylethanolamine-specific
αβ and γδ T cells in the blood of patients
with pollen allergies, although few clones expressed the canonical Vα24 TCR (72, 73).
Human melanomas overexpress the ganglioside GD3, and, on the basis of CD1d/
GD3 tetramer staining, immunization with
the human melanoma SK-MEL-28 was reported to expand a very small subset of Vα14
NKT cells in mice in vivo (74). These studies,
however, did not demonstrate a role for NKT
cells in rejection of GD3-overexpressing
tumors.
Another common glycosphingolipid,
β-galactosylceramide, was shown to induce
downregulation of NKT cell numbers and
TCR surface level in whole spleens examined
in vivo and in vitro (75). These effects were
relatively modest even at high concentrations
of lipids, and a direct stimulation or expansion
of cloned NKT cells could not be observed.
Because mice lacking β-galactosylceramide
(76) also did not exhibit NKT cell defects, the
physiological relevance of these observations
remains intriguing.
In summary, despite some exciting breakthroughs, this difficult and essential area of
study is somewhat controversial and remains
a work in progress. Owing to an array of criteria, including stimulation or staining by recombinant CD1d complexed with synthetic
ligands, lack of TLR signaling requirement,
stimulation of proliferation and cytokine secretion by large populations of fresh NKT
cells in mouse and human, and genetic or
functional indications of relevance in vivo during physiological processes and diseases, iGb3
and microbial α-glycuronylceramides represent the most compelling NKT ligands identified so far. Their identification considerably
reinforces the view that NKT cells and their
canonical mVα14-Jα18/hVα24-Jα18 TCRs
evolved to recognize conserved ligands and
to perform innate-like rather than adaptive
functions. The significance of other reported
individual specificities without functional correlates remains uncertain.
STRUCTURAL BIOLOGY OF
GLYCOLIPID RECOGNITION
Recent reports of the crystal structure of several CD1d/lipid complexes have far-reaching
implications. The lipid-binding pocket of
CD1d is particularly well adapted to bind
self and microbial glycosphingolipids, with
the acyl chain in the A hydrophobic pocket
and the sphingosin chain in the F hydrophobic channel (77–79). For αGalCer and the
closely similar α-glycuronylceramides, the α1
helix Arg79 and Asp80 establish hydrogen
bonds with the hydroxyl groups of the sphingosine. The α2 helix Asp153 stabilizes the
galactose through hydrogen bonds with the
2 and 3 hydroxyl group, solidly anchoring the protruding sugar in a position parallel to the plan of the α helices and explaining the exquisite stimulatory properties of
several hydroxyl groups (Figure 2). Because
α-anomeric glycosylceramides do not exist in
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Figure 2
Crystal structure of CD1d/αGalCer. (a) Transparent pocket view where the outer surface (light gray) of
CD1d has been partially removed to expose the binding groove inside (dark gray). The short αGalCer
PBS25 is found with the short C8 acyl chain in the A pocket and with the C18 sphingosine in the F
pocket. Note the deeply buried spacer C16 lipid at the bottom of the A pocket, likely originating from
the fly cell culture system where mouse recombinant CD1d was produced. (b) View of the α-anomeric
galactose sitting flat atop the groove. Molecular surfaces are presented with electrostatic potentials (red,
electronegative; blue, electropositive). The charged residues (Asp80, Arg79, and Asp153) involved in
hydrogen bonding with the hydroxyl groups of the carbohydrate and the sphingosine are indicated.
mammals, this structure represents a signature of microbial invasion.
Notably, CD1d produced in fly cells included a spacer lipid present at the bottom of
the A pocket, which preempted the loading
of full-length mammalian glycosphingolipid
and explained why in general short lipids
have proven easier to load onto CD1d in the
absence of lipid transfer proteins. However,
lipids with long and short (C8 ) acyl chain
produced identical conformations when complexed with CD1d, and they bound the TCR
with similar on and off rates (77, 80).
CD1d-iGb3 complexes have not yet been
reported, but modeling suggests that the
β-linked sugar should emerge orthogonal to
the plan of the α helices (77), which raises
the general issue of how the TCR will recognize two radically different structures and, in
particular, accommodate the three protruding
sugars. Intriguing insights have come from a
report that the human Vα24/Vβ11 TCR displays an unusual cavity between the CDR3 α
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and β loops (81), suggesting an unusual mode
of recognition of the trisaccharide within this
TCR cavity. Future crystallographic studies of
CD1d-iGb3 and ternary complexes with the
TCR should clarify these fundamental issues
and illuminate novel aspects of carbohydrate
recognition by immune receptors.
CELL BIOLOGY OF LIPID
PRESENTATION BY CD1d
CD1d is prominently and constitutively expressed by APCs such as DCs, macrophages,
and B cells (82, 83), particularly marginal zone
B cells (82), with relatively modest changes associated with TLR activation and inflammatory cytokines (84). CD1d is also strikingly
expressed on cortical thymocytes, where it is
essential for NKT cell development (18), and
on Kupffer cells and endothelial cells lining
liver sinusoids, where the highest frequencies of NKT cells are found in mice (30).
Hepatocytes express CD1d constitutively in
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mouse and upon disease induction in human,
for example, in the context of hepatitis C (85).
CD1d expression in the liver is not required,
however, for NKT cell homing (86), and neither is CXCR6 expression by NKT cells, although CXCR6/CXCL16 interactions are essential for survival in this organ (30). CD1d
is upregulated on microglial cells during inflammation (87). Similar to the MHC class
II system, most other solid tissue cells and
non-antigen-presenting hematopoietic cells
express low or undetectable levels of CD1d.
Trafficking of CD1d
The intracellular trafficking of CD1d has
been studied thoroughly (Figure 3). Biosynthesis of the heavy chain associated with
β2-microglobulin involves the endoplasmic
reticulum chaperones calnexin and calreticulin and the thiol oxidoreductase ERp57 (88).
It is logical to assume that endogenous lipids
in the endoplasmic reticulum would fill the
groove of CD1d, and one study suggested the
presence of phosphatidylinositol (45), with
the caveat that contamination by membrane
phospholipids could not be formally excluded.
CD1d rapidly reaches the plasma membrane
within 30 min after biosynthesis and undergoes extensive internalization and recycling
between the plasma membrane and endosomal/lysosomal compartments in a manner dependent upon a tyrosine motif encoded in the
CD1d cytoplasmic tail (89–91). The tyrosine
motif in the cytoplasmic tail primarily binds
adaptor protein (AP)-2 and AP-3 in mouse
(92, 93), where the bulk of CD1d accumulates in the lysosome, and AP-2 in humans,
where CD1d tends to reside in the late endosome (94). Additional but largely redundant contributions by the invariant chain or
invariant chain/MHC class II complexes that
bind weakly to CD1d have been documented
in mouse and human (89, 90). The CD1d
intracytoplasmic tail also expresses a lysine
targeted for ubiquitination by the MIR proteins of the Kaposi sarcoma–associated her-
pes virus, causing downregulation from the
cell surface without degradation (95). Interestingly, another herpes virus, herpes simplex
virus-1 (HSV-1), induces CD1d downregulation from the cell surface, but the mechanism appears to be distinct, involving lysosomal retention through impaired recycling to
the plasma membrane (96).
Intersection of CD1d and Lipids
in Late Endosome and Lysosome
Tail-truncated CD1d molecules fail to access
the late endosome and lysosome, causing a
profound disruption of CD1d-mediated antigen presentation in vitro in cell lines and in
vivo in knockin mice. Particularly affected are
the presentation of the NKT endogenous ligand (27) and, consequently, the thymic generation of Vα14 NKT cells (64). The presentation of diglycosylated αGalCer variants
requiring processing prior to NKT cell recognition, an important tool for research (56), or
of iGb4, which requires processing into iGb3
prior to recognition, is also abolished (26).
However, other lipids that do not require
processing still exhibit variable requirements
for the late endosome and lysosome trafficking of CD1d, either partial in the case
αGalCer (three- to fivefold shift in dose response) or substantial in the case of iGb3
(>10-fold shift). Recent studies of lipid uptake, trafficking, and loading have begun to
shed some light on these observations.
Lipid Uptake and Trafficking
Lipids in the circulating blood or in culture medium are bound to lipoproteins, and a
dominant role for VLDL in the serum and its
receptor, the LDL receptor, at the cell surface
has been proposed for the clathrin-mediated
uptake of some lipids into endosomal compartments (Figure 3) (97). Other extracellular
lipids can be captured by the mannose receptor langerin (98, 99) or can insert themselves directly in the outer leaflet of the
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Exogenous
lipid
iGb3
Vα14 TCR
Vα14 TCR
Exogenous
lipid
VLDL
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βHexB
AP-2/AP-3
LDLR
iGb4
iGb3
Saposins
Golgi
Late endosome/lysosome
MTP?
CD1d
ER
β2-m
Phagosome
Figure 3
Intracellular trafficking and lipid loading of CD1d. Newly biosynthesized CD1d molecules, likely
containing lipid chains, reach the plasma membrane and are internalized through an AP-2/AP-3
clathrin-dependent pathway to late endosomal/lysosomal compartments, where lipid exchange is
performed by saposins. The endogenous ligand iGb3 is produced through lysosomal degradation of iGb4
by β-hexosaminidase. CD1d extensively recycles between lysosome and plasma membrane, allowing
further lipid exchange. Exogenous lipids bound to lipoproteins may enter the cell with VLDL (very low
density lipoprotein) particles through the LDL receptor pathway, whereas microbial lipids can be
released in the lysosome after fusion with the microbial phagosome. Additional lipid exchange proteins
may be involved in these processes, particularly during biosynthesis, when a role for microsomal
triglyceride transfer protein (MTP) has been proposed.
plasma membrane and undergo endocytosis
through clathrin-dependent or -independent
pathways (100).
Glycosphingolipids tagged with a fluorochrome, BODIPY, on the acyl chain
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reached the late endosome and were rapidly
sorted to the endoplasmic reticulum and
the Golgi. In contrast, a prodan-conjugated
(on carbohydrate C6 ) αGalCer accumulated selectively in the lysosome (102). These
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pathways overlap only partially with those
governing the trafficking of endogenous glycosphingolipids, which are synthesized in the
lumenal part of the Golgi and thought to
reach the plasma membrane first, then the
endosome, through clathrin-dependent and
-independent endocytosis until they are degraded in the lysosome (103). How exogenously administered or endogenous intracellular lipids choose between these pathways
and the consequence for antigen presentation are questions that are just beginning to
be addressed and may depend on intrinsic
properties such as length or insaturation of
alkyl chains (104), composition of the polar head, and solubility in aqueous environments, as well as extrinsic variations in the
mode of administration such as use of detergents, liposomes, or lipid-protein complexes.
The development of new methodologies, genetic manipulation, and reagents will be required to address these essential questions. In
addition, recognition of microbial lipids in the
context of infection most likely involves different pathways because the uptake of bacteria
is governed by different sets of cell surface receptors and the release of cell wall lipids would
occur through degradation of the microorganism in the lysosome before processing and
loading onto CD1d.
Lipid Exchange Proteins
Although an intrinsic, pH-dependent mechanism appears to favor the acquisition of some
lipids by CD1 proteins, perhaps through a
conformational change (105, 106), lipid exchange now appears to be regulated by specialized lipid transfer proteins. By using various detergents, early studies of lipid binding to
CD1 molecules tacitly dealt with the fact that
in general lipids are insoluble in water, forming micelles that cannot transfer monomeric
lipids onto CD1. These detergents, however,
also tended to dislodge lipids bound to CD1,
as shown directly in the crystal structure of
CD1b complexed with phosphatidylinositol,
where two molecules of detergent cohabited
with the lipid in the groove (107). In contrast,
during biological processes, membrane lipids
are extracted and transported by lipid exchange proteins (108). Prosaposin is a protein
precursor to four individual saposins, A, B,
C, and D, released by proteolytic cleavage in
the lysosome. Prosaposin-deficient mice provided the first genetic link between NKT cells
and lipid metabolism, as they lacked NKT
cells and exhibited greatly impaired ability
to present various endogenous and exogenous NKT ligands (65, 66). In cell-free assays, recombinant saposins readily mediated
lipid exchange between liposomes and CD1d
in a nonenzymatic process requiring equimolar concentrations of CD1d and saposins (65).
Although they exhibited some overlap in lipid
specificity, individual saposins differed in their
ability to load particular lipids. More detailed studies of the effects of these and other
lipid exchange proteins such as NPC2 and
the GM2 activator are required to understand their function individually or cooperatively at different phases of lipid processing
and loading. In addition, the structural basis
of the lipid exchange mechanism and its relative specificity for lipid subsets remain to be
elucidated.
Another lipid transfer protein expressed
in the endoplasmic reticulum, microsomal
triglyceride transfer protein (MTP), assists in
the folding of apolipoprotein B by loading
lipids during biosynthesis. Coprecipitation of
MTP with CD1d suggested that MTP might
play a similar role for CD1 molecules (109).
Indeed, genetic or drug-induced inhibition of
MTP was associated with defects in lipid antigen presentation (109, 110). MTP was suggested to transfer phosphatidylethanolamine
onto CD1d in a cell-free assay, but the efficiency of this process remains to be established, and cell biological studies are required
in vivo to fully understand the role of MTP in
CD1d-mediated lipid presentation.
CD1e is a member of the human CD1 family that is not expressed at the plasma membrane but is instead found as a cleaved soluble
protein in the lysosome. Recent experiments
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have shown that CD1e could assist the
enzymatic degradation of phosphatidylinositolmannoside, suggesting that this protein
may have diverged from other CD1 molecules
to perform ancillary functions rather than
to carry out direct antigen presentation
(111).
Membrane Transporters
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NPC1 is a complex membrane multispan protein present in the late endosome that is mutated in Niemann-Pick type C1 disease and
associated with a lipid storage phenotype similar to NPC2, a soluble lipid transfer protein
present in the lysosome. NPC1-mutant mice
exhibited broad defects of NKT cell development and CD1d-mediated lipid presentation,
which could be attributed in part to an arrest
of lipid transport from late endosome to lysosome (102). The precise function of NPC1
remains unknown, and it is unclear how this
putative flippase translocating lipid between
leaflets of the membrane bilayer could induce
general alterations of lipid trafficking.
Other Glycosidases and Lipid
Storage Diseases
Mutations of several proteins involved in
glycosphingolipid degradation or transport
are accompanied by lipid storage within distended lysosomal vesicles, the impact of which
depends on the enzyme, the cell type, the
mouse strain, and the age at which cells
are examined (100, 101). This lipid accumulation may disrupt rate-limiting steps of
lipid metabolism and indirectly alter CD1mediated lipid antigen presentation through
defective lipid trafficking or lipid competition for loading CD1d. For example, while
NPC1-mutant cells showed a block in lipid
transport from late endosome to lysosome,
this block could be partially reversed by inhibitors of glycosphingolipid synthesis such
as N-butyldeoxygalactonojirimycin, presumably through alleviation of the lipid overload
(102). Bone marrow–derived DCs from mice
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lacking β-hexosaminidase B, α-galactosidase
A, or galactosylceramidase did not show
much alteration of general lipid functions
because they conserved their ability to process several complex diglycosylated derivatives of αGalCer for presentation to NKT
cells (26, 56, 65), although a divergent report was recently published (101). In contrast,
β-galactosidase-deficient cells exhibited more
general defects than expected from the specificity of the mutated enzyme ( J. Mattner and
A. Bendelac, unpublished data, and Reference
101).
Cathepsins
Paradoxically, studies of cathepsin-mutant
mice led to the first reports of defects in NKT
cell development and CD1d-mediated lipid
antigen presentation. This is particularly well
established for cathepsin L because mutant
thymocytes, but not DCs (perhaps owing to
the redundancy of other cathepsins), failed to
stimulate Vα14 NKT hybridomas in vitro and
consequently failed to select NKT cells in vivo
(112). Although its target remains to be identified, cathepsin L may be directly or indirectly
required for thymocytes to process prosaposin
into saposins.
NKT CELL DEVELOPMENT
Based on their canonical TCR receptors and
antigenic specificities, their unusual expression of NK lineage markers, their peculiar tissue distribution, and their functional properties independent of environmental exposure
to microbes, NKT cells constitute a separate lineage. Two models that explained the
basis of the NKT cell lineage were initially
opposed. One model suggested that NKT
cells originated from precursors committed
prior to TCR expression (committed precursor model), whereas the other model proposed
that the lineage was instructed after TCR expression and interaction with NKT ligands
(TCR instructive model). The first model was
based on a report suggesting the presence
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of cells expressing the canonical Vα14 TCR
at day 9.5 of gestation (113), well before a
thymus was formed, but these data have not
been reproduced with the new, more specific
CD1d tetramer reagents. Instead, the TCR
instructive model is now widely accepted on
the basis of the finding that although canonical Vα14-Jα18 rearrangements are rare and
stochastic (114), once expressed (e.g., in TCR
transgenic mice), an NKT TCR will induce
the full NKT cell lineage differentiation (115,
116).
Developmental Stages
The production of CD1d-αGalCer tetramers
specific for the canonical Vα14 TCRs (117–
119) has transformed this area of study by
allowing the identification of developmental steps independently of the expression
of NK1.1 (Figure 4). The first detectable
stages have a CD24high cortical phenotype and include a CD4intermediate CD8intermediate
(double-positive, DPdull ) stage, followed by
a CD4high CD8neg stage. These developmental intermediates immediately follow positive selection, as they express CD69 and are
not found in the CD1d-deficient thymus,
but they are present at extremely low frequencies (∼10−6 ) (120). The preselection DP,
observed easily in Vα14-Jα18 TCRα-chain
transgenic mice (115), still escape tetramer
detection in wild-type mice owing to the rarity of stochastic Vα14-Jα18 rearrangements
and the low TCR level at this stage. Investigators have attempted intrathymic transfer
of purified DP cells to demonstrate the presence of NKT cell precursors, but, given the
size of the inoculum (107 DP cells), these experiments could not formally rule out that
rare DN contaminants gave rise to the NKT
cell product (121). Interestingly, in mice lacking RORγt—a transcription factor induced in
DP thymocytes that is essential for prolonged
survival until distal Vα to Jα rearrangements (such as Vα14 to Jα18) can proceed—
NKT cell development was interrupted (122,
123).
As cells progress to the mature CD24low
stage, three more stages are described: first
a CD44low NK1.1neg stage (naive), then a
CD44high NK1.1neg (memory) stage, and finally a CD44high NK1.1pos (NK) stage (31,
124). This sequence is characteristically accompanied by a massive cellular expansion occurring between the CD44low NK1.1neg stage
and the CD44high NK1.1neg stage (125). This
expansion phase following positive selection
and leading to the acquisition of a memory
phenotype is in line with the innate role of
NKT cells, which requires high copy number
and effector/memory properties for prompt
and effective responses, but it represents a
key difference between the development of
NKT cells and that of conventional T cells.
Furthermore, during these stages a DN population arises by downregulation of CD4 in
∼30%–50% of the cells, as shown in cell
transfer experiments (120), and by genetic
fate mapping with ROSA26R reporter mice
crossed to CD4-cre deleter mice (123). DN
cells exhibit some functional differences with
CD4 cells, which are more pronounced in human than in mouse (126–128), and tend to
be more of the Th1 phenotype. The factors
determining this sublineage remain unclear,
as DN cells appear to share the same TCR
repertoire as the CD4 subset. A majority of
the CD44high NK1.1neg cells emigrate to peripheral tissues, where they stop proliferating and rapidly express NK1.1, a NK marker
available in the C57BL/6 background, followed by other NK lineage receptors such as
NKG2D, CD94/NKG2A, Ly49A, C/I, and
G2 (31, 32, 124). Thymic emigration assays using intrathymic injection of fluorescein
isothiocyanate have revealed that up to 5% of
recent thymic emigrants to the spleen, representing 5 × 104 cells, are CD44high NK1.1neg
NKT cells and rapidly acquire NK1.1 to join
the nondividing long-lived NK1.1+ pool of
∼5 × 105 cells (31, 32). Interestingly, a fraction of the CD44high NK1.1neg cells do not emigrate and instead proceed to terminal maturation (CD44high NK1.1pos ) inside the thymus,
where they become long-lived resident cells,
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DN
TCR/iGb3/CD1d
Vα14-Jα18
DN
RORγt
DP
Cortical
thymocytes
DP
SLAM/SLAM?
SAP/Fyn
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Bcl-xL
CD4
CD24hi
CD69hi
CD4
CD24lo
CD44lo
NK1.1–
IL-4
EC
CD4
CD4
DC
DN
CD4
MHC I
CD8
MHC II
PKCθ
Bcl-10
NF-κB
CD24lo
CD44hi
NK1.1–
IL-4
IFN-γ
T-bet
IL-15Rβ
CD4
DN
CD4
DN
Emigrant
Resident
CD1d
CD44hi
NK1.1+
IL-4
IFN-γ
TCR
Figure 4
Thymic NKT cell development. NKT cell precursors diverge from mainstream thymocyte development
at the CD4+ CD8+ double-positive (DP) stage. Upon expression of their canonical TCRα chain, which
requires survival signals induced by RORγt, NKT cell precursors interact with endogenous agonist
ligands such as iGb3, presented by CD1d expressed on other DP thymocytes in the cortex. Accessory
signals provided through homotypic interactions between SLAM family members recruit SAP and Fyn
to activate the NF-κB cascade. DP precursors downregulate CD8 to produce CD4+ cells, and a subset
later downregulates CD4 to produce CD4− CD8− double-negative (DN) cells. Unlike mainstream
T cells, NKT cell precursors undergo several rounds of cell division and acquire a memory/effector
phenotype prior to thymic emigration. Acquisition of NK lineage receptors, including NK1.1, occurs
after emigration to peripheral tissues, except for a minor subset of thymic NKT cell residents. The
transcription factor T-bet is required for induction of the IL-15 receptor β chain and survival at the
late-memory and NK1.1 stages. EC, epithelial cell; DC, dendritic cell.
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a peculiar fate of uncertain significance in the
mouse thymus (32) that may be absent in the
human thymus (129).
These developmental stages are associated with sharply defined functional changes.
Thus, the CD44low NK1.1neg cells are exclusive IL-4 producers upon TCR stimulation in vitro, whereas the CD44high NK1.1neg
cells produce both IL-4 and IFN-γ and the
CD44high NK1.1pos cells produce more IFN-γ
than IL-4 (31, 124). This is reflected faithfully
in the spontaneous expression of high levels of GFP (green fluorescent protein) by the
CD44low NK1.1neg and CD44high NK1.1neg
cells of IL-4-GFP “4get” knockin mice, and
in the expression of high levels of YFP (yellow
fluorescent protein) by the CD44high NK1.1pos
cells of IFN-γ-YFP “Yeti” knockins, which
reflect open chromatin in the corresponding
cytokine loci (130).
Because a panoply of NK receptors is expressed with kinetics and frequencies similar
to those of NK cells, components of a general NK lineage program are likely activated.
Interestingly, however, the extent and profile of NK receptor expression vary in different tissues, with thymic NKT cells expressing a repertoire similar to that of splenic NK
cells and spleen and liver NKT cells expressing these receptors at lower frequencies (131).
Whether these differences reflect different
stages of differentiation or an environmental influence on the acquisition or selection of
the NK receptor repertoire is not clear. Note
that, despite their potential to regulate TCR
signaling thresholds to antigen (132), including natural ligand (133), the functions of NK
receptors remain to be elucidated in a physiological context.
Contribution of T Cell Receptor Vβ
Chains to Natural Ligand
Recognition
TCR Vβ-Dβ-Jβ rearrangements occur at the
DN3 stage to produce a TCRβ chain that
pairs with the pre-Tα to form a receptor
that induces cellular expansion, allelic exclu-
sion at the β locus, and transition to the DP
stage, where rearrangements are initiated at
the TCRα locus. NKT cell precursors follow the same pre-Tα path as mainstream
T cells (120, 134). Therefore, the question
arises whether the biased usage of Vβ8, Vβ7,
and Vβ2 in mouse (and Vβ11 in human) is
due to the inability of the Vα14-Jα18 TCRα
chain to pair with the other Vβs or whether it
is due to positive or negative selection. Premature expression of a Vα14-Jα18 TCRα transgene at the DN3 stage created a population
of thymocytes with a broad Vβ repertoire,
ruling out a Vβ pairing issue (135). Of these
transgenic cells, however, only those expressing the biased Vβ set responded to iGb3,
whereas a broader set of Vβs responded to
αGalCer, demonstrating that the Vβ bias is
imparted by selection events. Furthermore,
Vβ7 cells responded to the lowest concentrations of iGb3, in agreement with several observations that Vβ7+ NKT cells are relatively
diminished upon CD1d overexpression (consistent with negative selection) and increased
upon CD1d underexpression (consistent with
decreased positive selection of the lower affinity Vβ8 and Vβ2) (62, 136, 137). Vβ7 cells
were also preferentially expanded in a fetal
thymic organ culture system after exposure
to exogenous iGb3 (62). Because the Vβ7 >
Vβ8 > Vβ2 affinity hierarchy of these Vβs
precisely reflects their respective degree of
enrichment during thymic selection, the Vβ
repertoire of NKT cells appears to be shaped
mainly by positive selection, with little contribution from pairing bias or negative selection
in natural conditions. However, NK lineage
T cells are not inherently resistant to negative
selection, as they tend to disappear in conditions of increased signaling (136, 138, 139).
Cellular Interactions
In contrast with MHC class I molecules,
mouse and human CD1d are induced at
the DP stage and downregulated at the
single-positive (SP) stage (82). This expression pattern explains why cortical thymocytes
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represent the thymic cell type, where CD1d
expression is necessary and sufficient for
NKT cell selection and lineage differentiation. Thus, NKT cells were absent in chimeric
mice lacking CD1d expression in the DP compartment (140). Conversely, in pLck-CD1d
transgenic and chimeric mouse models where
CD1d was exclusively expressed on cortical thymocytes, NKT cells developed nearly
normally and notably preserved their effector properties, with the exception of a relative decrease in NK receptor expression and
some hyperreactivity to TCR stimulation (86,
139). CD1d is also found on thymic CD11b+
macrophages, CD11c+ DCs, and epithelial
cells (86), but this expression appeared to play
only an auxiliary role in NKT cell development, as shown by the normalization of NK
receptor expression and TCR hyperreactivity upon crossing pLck-CD1d to Eα (MHC
class II)-CD1d mice. Interestingly, in another
Lck-CD1d transgenic model in which CD1d
was expressed at a high level on peripheral
T cells, NKT cells appeared to be hyporesponsive, and liver disease was observed (141).
Intrathymic transfer experiments and
thymic graft experiments further revealed that the acquisition of NK1.1 by
CD44high NK1.1neg NKT cells was decreased,
but not arrested, in the absence of CD1d
in the thymus or the periphery, although
life span and effector functions were relatively preserved (32). These observations
suggest that interactions with CD1d ligands
expressed by cell types other than DP occur
throughout NKT cell development in the
thymus and the periphery, consistent with
the autoreactivity of the Vα14 TCR, and,
although not absolutely required, they
nevertheless promote terminal NKT cell
differentiation.
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The above studies imply that an understanding of the NKT cell lineage commitment revolves around the signaling events imparted to
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gagement by CD1d-expressing cortical thymocytes. This signaling is expected to differ from that of conventional T cells for at
least two reasons. One is that the natural ligand is an agonist that would normally induce
negative selection in the mainstream lineage.
This is illustrated directly by the autoreactive IL-2 response of NKT hybridomas to
DP thymocytes (18) and by the proliferative
and cytokine response of fresh NKT cells to
synthetic iGb3 (26). The other reason is that
the developing NKT cell precursors interact with cortical DP thymocytes rather than
with epithelial cells, implying that homotypic
rather than heterotypic cellular contacts are
involved and therefore recruit accessory receptors or factors that elicit different signaling
pathways.
In this context, the reports that Fyn knockout (142, 143) and SLAM-associated protein
(SAP) knockout (144–146) mice lacked NKT
cells have attracted considerable attention because the Src kinase FynT was recently shown
to signal downstream of the SLAM family
of homotypic interaction receptors through
SAP (147–150). Several members of this family (151) are expressed on cortical thymocytes,
reinforcing the hypothesis of homotypic interactions signaling through SAP and FynT
during TCR recognition of CD1d ligands on
cortical thymocytes. Whether and which of
these SLAM family members are involved are
under investigation. In addition, the stages
at which these interactions might influence
NKT cell development and differentiation remain to be defined. Notably, the report that
a Vα14-Jα18 TCRα transgene corrected the
Fyn knockout–associated defect implied that
this stage would precede TCRα expression
(152), although interpretation of TCR transgenic results should be careful given the description of transgenic lineage artifacts (115,
135). Indeed, more recent studies in our laboratory indicate that this correction is partial
and due to the leaky phenotype of the Fyn
knockout because the SAP knockout was not
reconstituted (K. Griewank and A. Bendelac,
unpublished results).
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The emerging scenario, therefore, is that
homotypic interactions between SLAM family members initiated in the cortex during
Vα14 TCR engagement by CD1d/iGb3expressing cortical thymocytes lead to FynT
signaling after SAP recruitment to the cytosolic tyrosine motifs of SLAM family members (153). FynT signaling can activate the
canonical NF-κB pathway and may account,
in conjunction with TCR signaling, for the
well-established requirement of this pathway
in NKT cell development (Figure 4). Indeed, mice expressing a dominant-negative
IκBα transgene and those lacking NFκBp50 exhibited developmental arrest at the
CD44high NK1.1neg stage, which was partially
rescued by a Bcl-xL transgene, suggesting a
survival role for NF-κB (154, 155). The precise connections between TCR, FynT, and
NF-κB remain to be elucidated. PKCθ and
Bcl-10 have been implicated in the signaling
pathways of both FynT and the TCR leading
to NF-κB activation (156), and their ablation
impaired NKT cell development (157, 158),
although the NKT cell defects were relatively
modest. FynT has also been connected to
the Ras-GTPase-activating protein Ras-GAP
through the Dok1/2 adaptor proteins (149,
159), suggesting that signals emanating from
SLAM family members may regulate signaling downstream of the TCR to avoid negative selection through Ras while promoting
survival through NF-κB.
The molecular regulation of the NK program activated between CD44high NK1.1neg
and CD44high NK1.1pos cells remains enigmatic. The transcription factor T-bet induces
expression of the IL-2Rβ component of the
IL-15 receptor, which is important for the
survival of CD44high NK1.1neg and terminally
differentiated CD44high NK1.1pos cells (160–
162). However, the range of functions of
T-bet and its homolog eomesodermin in this
developmental pathway, particularly with respect to the induction of the NK differentiation program, remains to be investigated. Recent studies have suggested that Tec family
kinases Itk and Rlk play a central role in regu-
lating the decision between conventional and
NKT cell–like lineages. Thus, conventional
CD8 T cells lacking these kinases upregulated eomesodermin and the IL-15 receptor
and turned into NKT cell–like cells that required ligand on bone marrow–derived rather
than epithelial cells (163, 164). Interestingly,
mice expressing MHC class II molecules on
thymocytes through transgenic expression of
the transcription factor CIITA selected an unusual population of CD4 T cells resembling
NKT cells by their expression of a memory
phenotype (165).
Additional NKT cell precursor-intrinsic
factors regulate NKT cell development. For
example, mice lacking Runx1 (123) or Dock2
(166) or mice overexpressing BATF, a basic leucine zipper transcription factor and an
AP-1 inhibitor, exhibited severe defects early
in NKT cell development (167, 168).
Although NKT cells interact with cortical thymocytes rather than epithelial cells for
TCR/ligand and SLAM family interactions,
mice carrying defective components of the alternative NK-κB pathway, such as NIK or
Rel-B, in their thymic stroma exhibit severe
and early disruption of NKT cell development (155, 169). Because these mutations also
induce profound abnormalities of the thymus architecture, thymic lymphocyte emigration, and thymic DCs, there may be multiple
causes of the NKT cell defects (170). Lymphotoxin α1β2 (expressed on thymocytes)
signaling through the lymphotoxin β receptor
(expressed on stromal cells) can activate this
alternative pathway, but only modest NKT
cell defects have been reported in the corresponding mutant mice (171–173).
Finally, GM-CSF was reported to control
the effector differentiation of NKT cells during development by a mechanism that renders them competent for cytokine secretion
(174).
NKT CELL FUNCTIONS
NKT cells have been implicated in a
broad array of disease conditions ranging
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characterized a cascade of activation events
following the exogenous administration of
NKT ligands such as αGalCer (Figure 5).
The central feature is a reciprocal activation
of NKT cells and DCs, which is initiated
upon the presentation of αGalCer by resting DCs to NKT cells, inducing NKT cells
to upregulate CD40L and Th1 and Th2 cytokines and chemokines; CD40 cross-linking
induces DCs to upregulate CD40, B7.1 and
B7.2, and IL-12, which in turn enhances
NKT cell activation and cytokine production (175, 176). Propagation of this reaction
from transplant to tumors, various forms of
autoimmunity, atherosclerosis, allergy, and
infections.
NKT Cell Activation by
Administration of Ligand In Vivo
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The central concept underlying nearly all
NKT cell functions is the recognition by
the whole NKT cell population of endogenous ligands such as iGb3 (autoreactivity)
or of microbial cell wall glycolipids such as
α-glycuronylceramides. Several studies have
EC
Liver sinusoid
MΦ
CXCL16
IFN-γ
CD8
killer
CXCR6
NKT
IFN-γ
NK
IL-4,
IL-13
CD40L
CD40
Vα14
Jα18
CD1d:
lipid
IL-12
DC
B
CD4
helper
Figure 5
Cellular and molecular network activated by the NKT ligand αGalCer. DCs and perhaps also Kupffer
cells (macrophages) lining the liver sinusoids (where NKT cells accumulate) are at the center of a cellular
network of cross-activation, starting with NKT cell upregulation of CD40L, secretion of Th1 and Th2
cytokines and chemokines, and DC superactivation to prime adaptive CD4 and CD8 T cell responses.
NKT cells can provide help directly to B cells for antibody production and can also rapidly activate NK
cells. CXCR6/CXCL16 interactions provide essential survival signals for NKT cells. EC, endothelial cell.
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involves the activation of NK cell cytolysis
and IFN-γ production (177, 178) and, most
importantly, the upregulation of DC costimulatory properties and MHC class I– and
MHC class II–mediated antigen presentation,
particularly cross-priming, which serves as a
bridge to prime robust adaptive immune responses (179–181). Importantly, TLR signaling is not involved in these responses. Thus,
αGalCer and related variants are being actively investigated for their ability to serve
as vaccine adjuvants alone or in conjunction
with synergistic TLR ligands (182). In addition, the immunomodulatory properties of
repeated injection of NKT ligands may be
exploited to treat or prevent immunological
diseases (183).
Mature NKT cells produce massive
amounts of IFN-γ, but they are unique
among lymphocytes for their ability to explosively release IL-4 (184), in addition to other
key Th2 cytokines such as IL-13. The Th1
versus Th2 outcome of their activation is partially understood. Systemic injection of the
original αGalCer compound induces an early
burst of IL-4 detected in the serum, followed
by a more prolonged burst of IFN-γ by NKT
cells and transactivated NK cells, as well as of
IL-12 originating in part from DCs (185,
186). However, NKT cells also undergo a
rapid downregulation of their TCR, followed
by massive apoptosis within 3–4 days of activation, resulting in a long-lasting depletion
until regeneration occurs in part from thymic
precursors (187–189). More sustained and efficient responses have been described upon injection of αGalCer-pulsed DCs, particularly
with respect to the production of IFN-γ, resulting in a superior adjuvant effect for the
priming of cytotoxic T lymphocytes (CTL)
(190, 191).
Interestingly, some variants of the original
αGalCer KRN7000 have shown decreased
Th1 compared to Th2 cytokine induction.
These Th2 variants have shorter or insaturated lipid chains (185, 192, 193). The mechanisms underlying these differences are debated and may be diverse. Oki et al. (186)
proposed that the lipid with shorter sphingosin OCH failed to engage the TCR for a
long enough period of time to induce IFN-γ.
On the other hand, plasmon resonance determinations of TCR on and off rates, and even
crystal structures of the long (KRN7000) and
acyl shortened (PBS25, C8 acyl chain) version of αGalCer bound to CD1d have shown
no significant differences (77). An alternative
hypothesis is based on the observation that
different NKT ligands preferentially reach
different cell types upon injection in vivo, suggesting that increased Th1 responses may result from the predominant uptake of lipid by
IL-12-secreting cell types such as DCs (77,
194). Perhaps of relevance to this issue is the
fact that all Th2 ligands described so far have
increased solubility in water owing to their
shorter lipid tail or the presence of insaturations. This property could modify their routes
of trafficking and uptake, favoring presentation by non-IL-12-producing cells, such as
B cells. Finally, mucosal rather than systemic
modes of administration may also modify the
Th1/Th2 output of NKT cells owing to a preexisting bias in the cytokine environment.
Dual Reactivity to Self and Microbial
Ligands: A Paradigm for NKT Cell
Activation and Function During
Bacterial Infections
Glycosphingolipids closely related to
αGalCer were reported in the cell wall
of Sphingomonas (53, 54), a prominent
Gram-negative, LPS-negative member of
an abundant class of bacteria on Earth,
α-proteobacteria (Figure 6). Sphingomonas
is a ubiquitous bacterium whose cell wall
glycosphingolipids include the dominant
α-branched glucuronyl and galacturonyl
ceramides (GSL-1) and the less abundant di(GSL-2), tri- (GSL-3), and tetra- (GSL-4)
glycosylated species shown in Figure 1.
Although these glycosphingolipids form
structures reminiscent of LPS (Figure 6),
their synthesis pathway and role in the
microbial cell wall are not well understood.
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E. coli
LPS
Porin
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Figure 6
Lipid A
Outer membrane
Outer membrane
of the cell walls of
Sphingomonas and
Escherichia coli. The
inner leaflet of the
outer membrane is
composed of
phospholipids,
whereas the outer
leaflet is made of
LPS for E. coli. In
the case of
Sphingomonas,
glycosphingolipids
containing
between one and
four carbohydrates
substitute for LPS.
Note the thin layer
of peptidoglycan
separating the
inner and outer
membranes in both
cell walls.
Membrane proteins
Cytoplasm
Sphingomonas
Glycosphingolipids
Outer membrane
Cytoplasm
GSL-1 activates large proportions of mouse
and human NKT cells (23–25, 55), but it is
unclear at present whether the more complex
GSL-2, -3, and -4 can be recognized by NKT
cells or even whether they can be processed
efficiently into GSL-1 by host APCs.
During infection, Sphingomonas is phagocytosed by macrophages and DCs and elicits an activation cascade similar to exogenous
αGalCer. NKT cell activation enhances microbial clearance by 15- to 1000-fold within
the first 2–3 days of infection (23, 24).
Sphingomonas can also induce DC activation
through TLR-mediated signaling, but this
direct effect is weak relative to the crossactivation of DCs by NKT cells because
peptidoglycan and bacterial DNA are rela316
Peptidoglycan
Inner membrane
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Membrane proteins
Peptidoglycan
Inner membrane
tively weak stimulants. High doses of Sphingomonas induce a lethal toxic shock similar to the one associated with Gram-negative,
LPS-positive bacteria. However, in the case of
Sphingomonas, NKT cell–deficient mice are
protected. These striking observations have
led to the hypothesis that NKT cells and their
canonical TCR specificity evolved to meet
the challenges of these Gram-negative, LPSnegative bacteria. Although Sphingomonas is
a promiscuous bacterium that can cause severe infection, particularly in immunocompromised hosts, other more deadly members of the class of α-proteobacteria may
have provided stronger evolutionary pressures
on the NKT cell system. Particularly interesting is the case of Ehrlichia, a tick-borne
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lysosome, and by blocking experiments with
the lectin Griffonia simplicifolia IB4, which
recognizes the terminal sugar of the Galα13Gal epitope of iGb3 bound to CD1d and
blocks NKT cell activation (23). Strikingly,
NKT cell activation by Gram-negative, LPSpositive Salmonella is absolutely dependent
upon TLR signaling through the adaptors
MyD88 and Trif, and upon IL-12 release by
the APC, although the precise TLR combination and the corresponding microbial structures involved remain to be determined. Thus,
the proposed scenario suggests that TLR signaling leading, but not limited, to IL-12 secretion enhances the ability of DCs to stimulate
NKT cells through presentation of endogenous ligands (Figure 7).
Whether TLR signaling induces an upregulation of iGb3 or changes in the expression of other factors such as, for example, NK
receptor ligands is unclear. Contrary to an
early report (195), NKT cells do not usually
pathogen and member of the Rickettsiales that
is of widespread significance for mammals,
including wild and domesticated ruminants,
dogs, and humans from some regions of the
world such as Africa and East Asia. Ehrlichia
muris activates NKT cells independently of
iGb3, and its clearance was profoundly altered
in CD1d- or Jα18-deficient animals (23).
Ehrlichia is a Gram-negative, LPS-negative
obligate intracellular bacterium, whose cell
wall composition has not been elucidated.
Interestingly, many other bacteria, particularly the Gram-negative, LPS-positive ones,
can activate NKT cells. However, rather than
provide their own NKT ligands like Sphingomonas or Ehrlichia, these bacteria appear
to trigger autoreactive NKT cell responses
(23, 60). In the case of Salmonella, this is
suggested by the abrogation of NKT cell
activation in the presence of DCs lacking
β-hexosaminidase B, the enzyme responsible
for the generation of iGb3 from iGb4 in the
Direct microbial recognition
Indirect microbial recognition
IL-12p40
NKT cell
Gram-negative,
LPS-negative
bacteria
LPS
Bacterial Ag
iGb3
TLR4
Gram-negative
bacteria
?
Bacterial Ag
iGb3
Late endosome/lysosome
Figure 7
Dual recognition of self and microbial glycosphingolipids during microbial infections. On the left,
infection by Gram-negative, LPS-negative Sphingomonas induces direct activation of NKT cells through
recognition of microbial cell wall α-glycuronylceramide. On the right, infection by Gram-negative,
LPS-positive Salmonella activates TLR4 through LPS and induces IL-12, revealing constitutive
autoreactive recognition of iGb3 through the secretion of IFN-γ (indirect microbial recognition).
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constitute the predominant cell type that produces IFN-γ in response to IL-12 in vivo
(60, 196). This explains why they generally
do not appear to be essential in fighting
Gram-negative, LPS-positive bacteria. However, an impact on bacterial clearance has
been observed in the case of lung infection
with Pseudomonas aeruginosa, where CD1ddeficient mice exhibited a ∼20-fold increased
bacterial count in the lung within 6–24 h
postinoculation and an approximately threefold decrease in MIP-2 and neutrophils in the
bronchoalveolar lavage (197). This may not
be the case at other sites of infection (198).
Variations have been noted as well in reports
assessing the role of NKT cells versus NK
cells in LPS-induced toxic shock in vivo (199,
200).
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Primary Biliary Cirrhosis and
Sphingomonas
An intriguing connection between primary
biliary cirrhosis (PBC), Sphingomonas, and
NKT cells has emerged recently. PBC is a
disease characterized by the presence of antimitochondrial antibodies, liver lymphocytic
infiltrates, and the chronic destruction of the
biliary epithelium, which leads to cirrhosis
(201). Interestingly, the autoantibodies recognize an epitope of the mitochondrial PDCE2 enzyme that is particularly well conserved
in Novosphingobium aromaticivorans, a strain
of Sphingomonas. Furthermore, PBC patients,
including those lacking antimitochondrial antibodies, were specifically seropositive against
Sphingomonas, which was detected by PCR in
stool samples of 25% of diseased or healthy
individuals, suggesting that PBC may be induced by aberrant host reactivity to this bacterium (202). PBC patients also showed an enrichment of Vα24 NKT cells in liver biopsies,
but a depletion in blood (203). In light of the
recent finding that Sphingomonas cell wall glycolipids specifically activate NKT cells, these
studies suggest that NKT cells may play a key
role in the pathogeny of PBC by promoting
aberrant responses to Sphingomonas.
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Parasitic Infections
Shofield and colleagues (204) suggested that
the production of IgG antibodies to the
malaria circumsporozoite antigen, a key component of protective immune responses in
humans, depended on NKT cell recognition of malarial glycosylphosphatidylinositol antigens in a mouse model. However,
additional experiments failed to detect a
CD1d-dependent component to this antibody
response, and glycosylphosphatidylinositols
have not been identified as NKT cell antigens in other reports (205, 206). In the context of helminth infection, DCs pulsed with
Schistosoma mansoni eggs activated NKT cells
to secrete Th1 and Th2 cytokines in vitro in a
β-hexosaminidase-B-dependent but MyD88independent manner, suggesting recognition
of the self ligand iGb3 in the absence of TLR
signaling (207).
Viral Infections
Relatively modest defects in the clearance of
some viruses have been reported in CD1ddeficient mice infected with encephalomyocarditis virus (208) or coxsackie B3 (209),
but these defects were not observed in Jα18deficient mice, ruling out a specific role
of Vα14 NKT cells. Infections with lymphocytic choriomeningitis virus, mouse cytomegalovirus, vaccinia virus, and coronavirus
were unaffected. Studies in humans have suggested a profibrotic role of Vα24 NKT cells
in hepatitis C (85) and the accumulation of
non-Vα24 CD1d-restricted T cells (210). Although a specific role of Vα14 NKT cells
in HSV infection remains controversial (211,
212), recent studies have suggested that viral invasion may be associated with countermeasures against CD1d or NKT cells. For
example, HSV-1 drastically and specifically
impaired CD1d recycling from the lysosome
to the plasma membrane, an essential pathway
for glycolipid antigen presentation to NKT
cells (96). Kaposi sarcoma–associated herpes
virus encodes two modulators of immune
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recognition, MIR1 and MIR2, that downregulated CD1d in addition to other immunologically relevant molecules such as MHC class
I, CD86, and intracellular adhesion molecule
(ICAM)-1 through ubiquitination of lysine
residues in their cytoplasmic tail (95). The
lethal outcome of infections with EpsteinBarr virus in patients with X-linked lymphoproliferative (XLP) immunodeficiency syndrome due to SAP mutations was hypothesized to result from the absence of NKT cells
(144). Which of these effects or associations
reflect a specific viral evasion/immune defense
strategy and the nature of the NKT ligands involved in these infectious conditions remain
to be determined.
NKT Cells in Noninfectious
Diseases
A role of NKT cells has been suggested in a
wide variety of disease conditions. At present,
however, many reports, lacking a detailed
mechanistic understanding, remain isolated
or are based merely on the analysis of NKT
cell–deficient mice. Rather than compiling an
exhaustive list of the published claims, this review provides a critical appraisal of selected
reports carrying important conceptual or clinical implications. One frequently overlooked
but recurrent methodological issue inherent
in the use of CD1d- or Jα18-deficient mice
is the extent to which gene-deficient mice
are matched with littermate controls with respect to genetic background and environmental factors. This is particularly important in
studies of complex multigenetic diseases such
as diabetes, lupus, cancer, or asthma. In addition, the injection of αGalCer as a gainof-function experiment should be interpreted
with caution because the massive release of cytokines induced by this procedure is unlikely
to model chronic diseases. It may not be surprising, therefore, that some claims have become controversial or will need to be reinterpreted, complicating the task of drawing a
clear picture of the involvement of NKT cells
in noninfectious diseases.
Type I diabetes. The relative deficiency of
NKT cells in NOD mice (36, 37), combined
with the notion that these cells represent a potent source of Th2 cytokines, prompted the
original speculation of a causal relationship
with diabetes. Early claims that humans with
type I diabetes exhibited severe NKT cell defects and that their sera had less IL-4 than
controls (213, 214) were not confirmed when
more specific methodologies became available
(38, 215). Researchers interpreted reports of
aggravated disease in CD1d-deficient NOD
mice (216, 217) as suggesting that, although
defective, the residual NKT cells in NOD
mice still suppressed autoimmunity. However, independent studies in different colonies
of CD1d-deficient and Jα18-deficient mice
failed to support these claims (218), and partial reconstitution of NKT cells in NOD
mice carrying the B6 Nkt1 locus did not protect against diabetes (34). Transgenic expression of the Vα14-Jα18 TCRα chain in NOD
mice prevented diabetes, but this could be
explained by the reduced frequency of isletspecific T cells and the general Th2 bias of
these mice (219). Likewise, the suppression
of diabetes by αGalCer multi-injection regimens could be the mere consequence of massive cytokine release (220, 221). More direct transfer experiments using diabetogenic
T cells and NKT cells have suggested suppressive or enhancing roles of NKT cells
in different experimental systems (222, 223).
Although other more circumstantial studies
have suggested a role of NKT cells in this
disease, it seems reasonable to conclude at this
point that there is no decisive evidence for a
substantial or specific role of NKT cells in
mouse or human type I diabetes.
Lupus. Hyperreactive NKT cells were
shown to accumulate in aging NZB/W mice
(224) and suggested to help B cells produce
anti-DNA antibodies (225). However, studies
of CD1d-deficient lupus-prone mice have
not yielded concordant results (226–228),
and injections of αGalCer ameliorated or
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aggravated disease, depending on the mouse
strain (229).
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Cancer. Similar to the general immune suppression of T cells commonly encountered in
cancerous states, NKT cells were decreased or
functionally hyporeactive in cancer-bearing
mice and humans (230, 231). One tumor shed
glycosphingolipids that could inhibit the stimulation of NKT cells in vitro (232). However, multiple mechanisms are likely to contribute to the deficiency of both T and NKT
cells. In one report, the frequency of sarcomas
six months after intramuscular injection of
the chemical carcinogen methylcholantrene
(MCA) decreased two- to threefold in Jα18
knockout NKT cell–deficient mice (233).
This observation, which suggested that NKT
cells, similar to γδ T cells and NK cells, may
be agents of immune surveillance against primary cancers has remained isolated.
In a tumor transplant model, subcutaneous
injection of a fibrosarcoma tumor line derived
from MCA-inoculated Jα18-deficient mice
produced tumors that grew faster in Jα18deficient compared with wild-type mice and
were prevented by transfers of purified NKT
cells into Jα18-deficient hosts (234). CD1d
expression and the presence of CD8 T cells
in the host were required for tumor rejection,
implying ligand recognition on host-derived
cells, presumably APCs, rather than on tumor cells. The nature of the tumor-associated
NKT ligands has not been identified. These
experiments also revealed a specialized function of liver DN—as compared with CD4—
NKT cells in this Th1-mediated response
(128).
In apparent contrast with this fibrosarcoma model, CD1d-deficient mice controlled
the growth of otherwise relapsing subcutaneous transplants of the 15-12RM tumor line,
suggesting that a natural CD1d-dependent
mechanism suppressed tumor rejection (235).
Further studies dissected a complex cellular network that involved IL-13-producing
CD1d-restricted CD4 suppressors interacting with TGF-β-producing myeloid cells to
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suppress antitumor CTL responses. Because
Jα18-deficient mice did not share the phenotype of CD1d-deficient mice, the study concluded that other less well-known types of
CD1d-restricted T cells might be involved
(236). As in the MCA-induced tumor transplants, these tumors did not express CD1d,
yet CD1d expression by host cells, presumably
APCs, was required to observe the NKT cell
effects. In contrast, the growth of the CD1dtransfected RMA/S tumor cell line cells was
inhibited by Vα14 NKT cells (237). In conclusion, the notion that mVα14 and hVα24
NKT cells regulate cancer rejection is based
largely on tumor transplant models, and the
relevance to natural clinical conditions remains to be determined.
Asthma. CD1d- and Jα18-deficient mice
were reported to exhibit decreased allergeninduced airway hyperreactivity in the alumovalbumin model of asthma, where mice are
intraperitoneally sensitized with ovalbumin
mixed in alum and subsequently challenged
with ovalbumin inhalation (238, 239). However, similar studies in another laboratory
have failed to observe differences between
CD1d-deficient and wild-type mice (R. Locksley, personal communication). In humans
with persistent, moderate-to-severe asthma,
Vα24 NKT cells dominated the bronchial
Th2 infiltrate (240). The extent of this NKT
cell expansion has been disputed, however,
perhaps reflecting differences in the cohorts
of asthma patients examined or the methods
for identifying NKT cells (241).
Atherosclerosis. CD1d deficiency decreased the level of atherosclerosis in apoEor LDL receptor–deficient mice, although
the effects observed were only mild and
transient in some studies (241, 242).
Other disease conditions. Additional observations suggesting a suppressive role of
NKT cells in some models of delayedtype hypersensitivity (242, 243), in anterior
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chamber–associated immune deviation (244),
and in burn injury (245) have been reported.
In summary, contrasting with numerous
reports suggesting a contribution of NKT
cells in a range of noninfectious diseases, a
convincing picture has not yet emerged as to
the strength or consistency of the observed
effects, their mechanisms, or their relevance
to physiological or clinical conditions. Future
experiments are needed to define those diseases and conditions that are regulated specifically by mVα14 or hVα24 NKT cells and to
dissect the mechanisms involved.
THE LARGER CD1 UNIVERSE
Although T cells recognizing lipids presented by other CD1 isotypes were the first
discovered (44), their study now represents
only a small fraction of the current investigations on CD1-mediated antigen presentation, which focus overwhelmingly on
the CD1d/NKT cell system. CD1d is the
only representative in mouse and rat of a
larger family of β2-microglobulin-associated
MHC-like molecules that, in other mammalian species, comprises CD1a, -b, and -c,
as well as CD1e (44). CD1 and MHC are encoded in different loci, but recent genomic
studies in chicken suggest that they originated
from the same primordial MHC locus (246).
CD1a, -b, and -c differ in their location in
different endosomal compartments, in early
recycling to late endosome and lysosome, and
also in the architecture of their lipid-binding
grooves, which suggests that each is specialized to capture different lipids in different endosomal compartments (44). Individual self
and microbial lipid-specific T cell clones have
been derived in vitro in humans, but relatively
little is known about the T cell types and TCR
repertoires associated with CD1a, -b, and -c
and about their function in the human system.
With respect to CD1d, however, it is
well established that the major population of
CD1d-restricted T cells in mouse is the NKT
cell population that expresses semi-invariant
TCRs, predominantly Vα14-Jα18, and per-
forms innate-like functions (19). The presence of a more diverse population has been
suggested recently, more convincingly in humans, indicating that an adaptive population
of lipid-specific CD1d-restricted T cells may
be available (210, 247, 248). The biology of
these cells remains largely unexplored, and future studies in this area would resolve a fascinating and long-standing debate in the field
of T cell recognition. Indeed, glycolipids are
not easily mutated or modified, and although
the potential theoretical combinations of carbohydrates are extremely diverse, the universe
of microbial glycolipids is limited owing to enzyme specificity for both donor and acceptor
substrates in glycolipid synthesis. Thus, the
glycolipid-specific repertoire did not evolve
under the same pressure that operated on the
peptide-specific repertoire, where single mutations produce new T cell epitopes. How
diverse and specific this glycolipid-specific
repertoire may be is an important question
for future research because conserved glycolipids may represent ideal, fixed targets for
vaccine development. In addition, how crossreactive the MHC- and CD1-restricted TCR
repertoires are is a fundamental issue that
remains to be investigated. Given that the
groove of CD1 molecules is significantly narrower than that of MHC proteins and that at
least a proportion of the TCR repertoire appears to be intrinsically MHC-restricted (249,
250), one would assume that the peptidespecific and glycolipid-specific TCR repertoire should be essentially non-cross-reactive,
a prediction that remains to be tested.
SUMMARY
Recent studies have elucidated novel and
striking aspects of NKT cell development
and of the cell and structural biology of
lipid antigen processing and recognition. Key
candidate antigens have been identified that
provide a framework for understanding the
evolution and function of this innate-like lineage, particularly in microbial infections. Future work will clarify the range and nature
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of the most physiologically relevant ligands
and the structural basis of their recognition
by the semi-invariant TCRs. These solid advances in fundamental biology should help
develop a mechanistic understanding of the
broad and sometimes controversial array of
diseases in which NKT cells are increasingly
implicated.
ACKNOWLEDGMENTS
Annu. Rev. Immunol. 2007.25:297-336. Downloaded from arjournals.annualreviews.org
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We thank past and present members of our laboratories for their contributions to the understanding of NKT cell biology; Seth Scanlon and Omita Trivedi, for help with the figures;
and Richard Locksley, Diane Mathis, and Thomas Blankenstein for sharing unpublished results. Dirk Zajonc generated the structural representation in Figure 2. This work is supported
by the Howard Hughes Medical Institute (A.B.) and by a program project grant from the
National Institutes of Health (A.B., P.B.S., L.T.). No review on NKT cell biology can adequately describe every interesting paper, and we apologize to those investigators whose work
could not be cited because of space limitations.
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Contents
Volume 25, 2007
Frontispiece
Peter C. Doherty p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x
Challenged by Complexity: My Twentieth Century in Immunology
Peter C. Doherty p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1
The Impact of Glycosylation on the Biological Function and Structure
of Human Immunoglobulins
James N. Arnold, Mark R. Wormald, Robert B. Sim, Pauline M. Rudd,
and Raymond A. Dwek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 21
The Multiple Roles of Osteoclasts in Host Defense: Bone Remodeling
and Hematopoietic Stem Cell Mobilization
Orit Kollet, Ayelet Dar, and Tsvee Lapidot p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 51
Flying Under the Radar: The Immunobiology of Hepatitis C
Lynn B. Dustin and Charles M. Rice p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 71
Resolution Phase of Inflammation: Novel Endogenous
Anti-Inflammatory and Proresolving Lipid Mediators and Pathways
Charles N. Serhan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p101
Immunobiology of Allogeneic Hematopoietic Stem Cell
Transplantation
Lisbeth A. Welniak, Bruce R. Blazar, and William J. Murphy p p p p p p p p p p p p p p p p p p p p p p p139
Effector and Memory CTL Differentiation
Matthew A. Williams and Michael J. Bevan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171
TSLP: An Epithelial Cell Cytokine that Regulates T Cell
Differentiation by Conditioning Dendritic Cell Maturation
Yong-Jun Liu, Vasilli Soumelis, Norihiko Watanabe, Tomoki Ito,
Yui-Hsi Wang, Rene de Waal Malefyt, Miyuki Omori, Baohua Zhou,
and Steven F. Ziegler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p193
Discovery and Biology of IL-23 and IL-27: Related but Functionally
Distinct Regulators of Inflammation
Robert A. Kastelein, Christopher A. Hunter, and Daniel J. Cua p p p p p p p p p p p p p p p p p p p p p p221
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Improving T Cell Therapy for Cancer
Ann M. Leen, Cliona M. Rooney, and Aaron E. Foster p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p243
Immunosuppressive Strategies that are Mediated by Tumor Cells
Gabriel A. Rabinovich, Dmitry Gabrilovich, and Eduardo M. Sotomayor p p p p p p p p p p p p267
The Biology of NKT Cells
Albert Bendelac, Paul B. Savage, and Luc Teyton p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p297
Annu. Rev. Immunol. 2007.25:297-336. Downloaded from arjournals.annualreviews.org
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Regulation of Cellular and Humoral Immune Responses by the SLAM
and SAP Families of Molecules
Cindy S. Ma, Kim E. Nichols, and Stuart G. Tangye p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p337
Mucosal Dendritic Cells
Akiko Iwasaki p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p381
Immunologically Active Autoantigens: The Role of Toll-Like
Receptors in the Development of Chronic Inflammatory Disease
Ann Marshak-Rothstein and Ian R. Rifkin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p419
The Immunobiology of SARS
Jun Chen and Kanta Subbarao p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p443
Nonreceptor Protein-Tyrosine Phosphatases in Immune Cell Signaling
Lily I. Pao, Karen Badour, Katherine A. Siminovitch, and Benjamin G. Neel p p p p p p p473
Fc Receptor-Like Molecules
Randall S. Davis p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p525
The Death Domain Superfamily in Intracellular Signaling of Apoptosis
and Inflammation
Hyun Ho Park, Yu-Chih Lo, Su-Chang Lin, Liwei Wang, Jin Kuk Yang,
and Hao Wu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p561
Cellular Responses to Viral Infection in Humans: Lessons from
Epstein-Barr Virus
Andrew D. Hislop, Graham S. Taylor, Delphine Sauce, and Alan B. Rickinson p p p p p p587
Structural Basis of Integrin Regulation and Signaling
Bing-Hao Luo, Christopher V. Carman, and Timothy A. Springer p p p p p p p p p p p p p p p p p p p619
Zoned Out: Functional Mapping of Stromal Signaling
Microenvironments in the Thymus
Howard T. Petrie and Juan Carlos Zúñiga-Pflücker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p649
T Cells as a Self-Referential, Sensory Organ
Mark M. Davis, Michelle Krogsgaard, Morgan Huse, Johannes Huppa,
Bjoern F. Lillemeier, and Qi-jing Li p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p681
The Host Defense of Drosophila melanogaster
Bruno Lemaitre and Jules Hoffmann p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p697
vi
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Ontogeny of the Hematopoietic System
Ana Cumano and Isabelle Godin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p745
Chemokine:Receptor Structure, Interactions, and Antagonism
Samantha J. Allen, Susan E. Crown, and Tracy M. Handel p p p p p p p p p p p p p p p p p p p p p p p p p p787
IL-17 Family Cytokines and the Expanding Diversity of Effector
T Cell Lineages
Casey T. Weaver, Robin D. Hatton, Paul R. Mangan, and Laurie E. Harrington p p p821
Annu. Rev. Immunol. 2007.25:297-336. Downloaded from arjournals.annualreviews.org
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Indexes
Cumulative Index of Contributing Authors, Volumes 15–25 p p p p p p p p p p p p p p p p p p p p p p p p853
Cumulative Index of Chapter Titles, Volumes 15–25 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p860
Errata
An online log of corrections to Annual Review of Immunology chapters (if any, 1997 to
the present) may be found at http://immunol.annualreviews.org/errata.shtml
Contents
vii