Download CD1d Ligands: The Good, the Bad, and the Ugly

CD1d Ligands: The Good, the Bad, and the
Ugly
Randy R. Brutkiewicz
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References
J Immunol 2006; 177:769-775; ;
doi: 10.4049/jimmunol.177.2.769
http://www.jimmunol.org/content/177/2/769
OF
THE
JOURNAL IMMUNOLOGY
BRIEF REVIEWS
CD1d Ligands: The Good, the Bad, and the Ugly1
Randy R. Brutkiewicz2
I
t is said that looks are not everything. Nonetheless, how
things look (i.e., structure) can have profound effects on
biological functions. The folding and overall structure of
MHC class I and class I-like molecules possessing activities
ranging from Ag presentation (1) to the transport of maternal
Abs via a neonatal FcR (2– 4) to iron transport (5), demonstrate
that this particular “look” goes a long way, and is thus critical.
The majority of these molecules are involved in Ag presentation. In addition to the MHC class I and class II Ag presentation pathways, the presentation of nonpeptidic ligands (almost
all are lipids) occurs by CD1 molecules. The CD1 family consists of two groups based on amino acid homology (6): group 1
includes CD1a, b, and c, whereas CD1d is the sole member of
group 2. In the mouse, there are two CD1d molecules, CD1d1
and CD1d2. Although the group 1 CD1 molecules can present
Ags to a wide variety of T cells, CD1d molecules present their
Ags mostly to a unique T cell subpopulation called NKT cells.
The majority of these T cells are called canonical or invariant
NKT (iNKT3 cells) with a specific TCR ␣-chain rearrangement (V␣14-J␣18 in mice; V␣24-J␣18 in humans), associated
with V␤ chains of limited diversity. NKT cells are capable of
Department of Microbiology and Immunology, Indiana University School of Medicine,
Indianapolis, IN 46202; and The Walther Oncology Center, Walther Cancer Institute,
Indianapolis, IN 46208
Received for publication March 25, 2006. Accepted for publication May 5, 2006.
The costs of publication of this article were defrayed in part by the payment of page charges.
This article must therefore be hereby marked advertisement in accordance with 18 U.S.C.
Section 1734 solely to indicate this fact.
1
This work was supported in part by National Institutes of Health Grants AI46455,
CA89026, and AI056097, as well as support from the Walther Cancer Institute. R.R.B. is
a Scholar of the Leukemia and Lymphoma Society.
Copyright © 2006 by The American Association of Immunologists, Inc.
producing both Th1 and Th2 cytokines rapidly upon activation, suggesting that they have important immunoregulatory
functions. This subject has been reviewed recently (7), so I will
not discuss it further here. Both group 1 and group 2 CD1 molecules can present lipids (and perhaps other molecules) to the
immune system (8), with those presented by CD1a, b, and c
more extensively studied to date (with CD1d catching up very
rapidly). Thus, the objective of this review is to discuss what is
known about those molecules presented by CD1d and what (if
any) activity the presentation of these ligands by CD1d in various disease states has been demonstrated. Some of these CD1dpresented ligands can activate T cells (good), some are inhibitory (bad), and some are not lipids (ugly?).
Natural, endogenous CD1d ligands
In 1997, the first report suggesting that CD1d could present Ag
demonstrated that a hydrophobic peptide called p99 could
bind to murine CD1d1 and stimulate CD8⫹ T cells generated
against the CD1d1/p99 complex (9). Interestingly, 2 years
later, the crystal structure of CD1d1 was solved, and it indeed
possessed a highly hydrophobic Ag binding groove (10). However, in 1998, we (Sebastian Joyce, Robert Cotter, Amina
Woods, Jonathan Yewdell, Jack Bennink, and I) extracted a
natural ligand from CD1d1 (11). Rather than a peptide (which
is frankly what we had anticipated we would find), we detected
GPI as a major natural ligand (Fig. 1). We went on to show that
phosphatidylinositol (PI) is also bound (12). Similarly, it was
found that PI is a ligand naturally bound to human CD1d as
well (13). More recently, CD1d1 was found to have phosphatidylcholine (PC) bound in a crystal structure derived from
CD1d1 secreted from Drosophila cells (14). Thus, glyco- and
phospholipids are natural ligands bound to CD1d molecules.
What is their purpose in the grand scheme of CD1d-mediated
Ag presentation? Although these molecules can bind to CD1d,
they can only in rare circumstances stimulate canonical NKT
cells (15). We suspected that the role they play is analogous to
the function played by the invariant chain-derived CLIP peptide for MHC class II-mediated Ag presentation. Thus, the natural, endogenous glyco- and phospholipids reside in the CD1d
2
Address correspondence and reprint requests to Dr. Randy R. Brutkiewicz, Department
of Microbiology and Immunology, Indiana University School of Medicine, Building R2,
Room 302, 950 West Walnut Street, Indianapolis, IN 46202-5181. E-mail address:
[email protected]
3
Abbreviations used in this paper: iNKT, invariant NKT; PI, phosphatidylinositol; PC,
phosphatidylcholine; iGb3, isoglobotrihexosylceramide; EAE, experimental allergic encephalomyelitis; ␣-GalCer, ␣-galactosylceramide; ␤-GalCer, ␤-galactosylceramide;
OCH, ␣-GalCer with a truncated sphingosine chain; GSL-1, ␣-glucuronosylceramide;
PIM, phosphatidylinositol mannoside; PPBF, phenyl pentamethyldihydrobenzo
furansulfonate.
0022-1767/06/$02.00
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The MHC class I-like CD1d glycoprotein is a member of
the CD1 family of Ag-presenting molecules and is responsible for the selection of NKT cells. A number of ligands
that can be presented by CD1d to NKT or other CD1drestricted T cells have been identified. These include glycolipids from a marine sponge, bacterial glycolipids, normal endogenous glycolipids, tumor-derived phospholipids
and glycolipids, and nonlipidic molecules. The presentation of many of these molecules can have immunopotentiating effects, such as serving as an adjuvant against malaria or resulting in a more rapid clearance of certain
virus infections. They can also be protective in autoimmune diseases or cancer or can be deleterious. This review
will highlight these ligands in a discussion of their potential use against (and role in the pathogenesis of) these
diseases. The Journal of Immunology, 2006, 177:
769 –775.
770
BRIEF REVIEWS: CD1d LIGANDS—THE GOOD, THE BAD, AND THE UGLY
Ag binding groove until in the correct (presumably late endocytic) compartment, where these ligands are replaced by a
(glyco)lipid that, when presented on the cell surface by CD1d,
stimulate NKT cells (16 –18). For MHC class II molecules, the
exchange of CLIP for an antigenic peptide in the MIIC compartment requires an acidic pH environment (19). Similarly,
we found that inhibiting such acidification in these compartments substantially impairs CD1d-mediated Ag presentation
(16). In line with our observations, Luc Teyton and Albert Bendelac, and Peter Cresswell independently showed direct evidence for such an exchange of an endogenous CD1d ligand mediated by a family of lipid transfer proteins termed saposins (20,
21). Soon after these reports, the Bendelac laboratory found
that isoglobotrihexosylceramide (iGb3), a lysosomal glycosphingolipid, is a natural CD1d-presented ligand that can stimulate NKT cells (22). In mice deficient in the enzyme ␤-hexosaminidase b, important for iGb3 generation, NKT cell
development is impaired substantially (22). In contrast to that
which occurs with iNKT cells, some noncanonical NKT cells
appear to be able to recognize lipids that are potentially loaded
onto CD1d in the endoplasmic reticulum (20, 21, 23–26).
Some natural cellular lipids can bind to CD1d and stimulate
NKT cells or other CD1d-restricted T cells; several of these
have effects in various disease states. For example, the natural
lipid sulfatide found in myelin is presented by the group 1 CD1
molecules CD1a, b, and c (27, 28). This has important relevance in multiple sclerosis, as autoimmune responses to myelin
occur in these patients, and such responses are believed to contribute to disease pathogenesis. In a mouse model, it has been
shown that sulfatide can be presented by CD1d to T cells other
than NKT cells, as determined by the use of sulfatide-loaded
CD1d1 tetramers (29). Furthermore, and most importantly,
treatment of wild-type (but not CD1d-deficient) mice with sulfatide prevented the development of experimental allergic encephalomyelitis (EAE) in that study. The recent solving of the
crystal structure of CD1d1 complexed with sulfatide (30) will
be helpful in understanding how this lipid is presented to
CD1d-restricted, sulfatide-specific T cells.
Two natural lipid components of the cell membrane, the disialoganglioside GD3 and PI, have been shown to be CD1dpresented Ags capable of stimulating (at least some) NKT cells.
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FIGURE 1. “Natural” ligands of
CD1d. An array of lipids derived from
mammalian cells that can bind to
CD1d and stimulate or inhibit (or not
activate) CD1d-restricted T cells.
Gg3Cer, gangliotriaosylceramide; PE,
phosphatidylethanolamine.
The Journal of Immunology
FIGURE 2. ␣-GalCer and ␣-GalCer
analogs. Synthetic ␣-GalCer and ␣-GalCer-based glycolipids used in studies described in this review.
Lipids binding to CD1d can also have inhibitory functions.
As a case in point, the murine T cell lymphoma line L5178Y-R
sheds glycolipids, with gangliotriaosylceramide being predominant (33, 34). We found that gangliotriaosylceramide inhibited CD1d-mediated Ag presentation to NKT cells (35), suggesting one means by which a tumor can evade an important
component of the innate antitumor immune response.
␣-Galactosylceramide (␣-GalCer) and ␣-GalCer analogs
In 1997, a group led by Masaru Taniguchi found that ␣-GalCer, a glycolipid extracted from the marine sponge Agelas mauritianus (36), could stimulate NKT cells to rapidly produce
both Th1 and Th2 cytokines in a CD1d-dependent manner (7,
37). ␣-GalCer has an ␣-anomeric sugar attached to acyl and
sphingosine chains (Fig. 2). ␣-GalCer-mediated stimulation of
NKT cells interestingly results in an internalization of the TCR
(38 – 40), originally thought to be a “loss” (41– 46). The
Kawano et al. (37) study opened a floodgate of reports showing
that ␣-GalCer could be effective as an antitumor immunopotentiator in a wide range of tumor model systems (reviewed in
Ref. 47), as well as in other disease states. For example, in the
murine B16 melanoma, or those tumors induced by methylcholanthrene, the administration of ␣-GalCer to tumor-bearing mice had profound in vivo effects by inhibiting metastatic
disease, as well as the elimination of the primary tumor. Analysis of the antitumor efficacy of ␣-GalCer, coupled with the
site-directed mutagenesis of the murine CD1d1 molecule (48),
helped increase our understanding of how ␣-GalCer bound to
CD1d and also provided clues regarding the mechanisms behind NKT cell activation by this glycolipid. ␣-GalCer was also
shown to inhibit or ameliorate autoimmune diseases including
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In the case of GD3 derived from the melanoma line SK-MEL28, it appears as though it can be cross-presented by murine
APCs to NKT cells (31). Furthermore, injection of GD3 into
wild-type (but not CD1d-deficient) mice resulted in an increased number of NKT cells in the spleen, and these were detectable using GD3-loaded CD1d1 dimers. In the case of PI,
one NKT cell hybridoma out of a panel of nine expressing an
invariant TCR ␣-chain (V␣14J␣18) was strongly stimulated by
soybean-derived PI when added to plate-bound purified
CD1d1 (15). This NKT cell hybridoma called 24.8.A (and
none of the others) was also stimulated to various degrees by
phosphatidylethanolamine, phosphatidic acid, phosphatidylserine, phosphatidylinositol, PC, and monogalactosyl diglyceride. Furthermore, 24.8.A was able to recognize cd1d1 cDNAtransfected murine P815 (mastocytoma), EL-4, RMA/S (both
T cells), and A20 (B cell) tumor cell lines (15). Of note, this
group went on to show that changes in the degree of unsaturation of the phosphatidylethanolamine (the CD1d-presented Ag
best able to stimulate 24.8.A) acyl chain affected its recognition
by the NKT cell hybridoma. This is consistent with acyl chain
structure playing an important role in phospholipid Ag presentation by CD1d (32). Interestingly, the 24.8.A NKT cell hybridoma could also “see” purified CD1d1 without added ligand. However, with a recent report showing that the crystal
structure of Drosophila cell-expressed CD1d1 contains PC as a
natural ligand (14), perhaps CD1d is never really “empty,” and
this result may have been predictable in hindsight. Regardless of
the very wide range of Ags recognized by this particular NKT
cell hybridoma, it is nonetheless an interesting example of
CD1d-presented ligands and their ability to be recognized by
components of the innate immune response.
771
772
BRIEF REVIEWS: CD1d LIGANDS—THE GOOD, THE BAD, AND THE UGLY
Endogenous microbial NKT cell “activators”
Last year, three groups independently found that a predominant glycosphingolipid from the LPS-free Sphingomonas (S.
capsulata, S. paucimobilis, and S. wittichii) and Ehrlichia muris
bacteria could stimulate human and/or murine NKT cells in a
CD1d-dependent manner (78 – 81). All of these groups identified ␣-glucuronosylceramide (GSL-1) as this glycosphingolipid, with ␣-galacturonosylceramide also able to activate NKT
cells (78, 79). Interestingly, in the case of S. paucimobilis, the
tetraglycosylated glycosphingolipid from S. paucimobilis (not or
poorly recognized by NKT cells) is processed into the active
GSL-1 in low pH compartments, probably lysosomes (80). The
relative ease in the purification of GSL-1 from the bacteria (and
the lack of LPS substantially helps) extends the number of laboratories who can use this ligand in their studies. An additional
unique aspect of GSL-1 as opposed to ␣-GalCer is the NKT cell
populations identified by CD1d1 tetramers or dimers loaded
with this glycolipid. Approximately one-half of those NKT cells
that are ␣-GalCer/CD1d1 tetramer positive are GSL-1/CD1d1
dimer (or tetramer) positive. Furthermore, the demonstration
that the clearance of these bacteria from animals that are NKT
cell deficient is impaired (78, 79) shows that GSL-1 presentation by CD1d is important in a pathogen model system. Thus,
GSL-1 is not simply “just another CD1d ligand.”
Two other sources of microbial products have been shown to
be able to activate NKT cells. The Bonneville and Schaible
groups reported that PI mannoside (PIM) could stimulate both
human and murine NKT cells (82). Additionally, PIM-loaded
CD1d tetramers could stain both human (PBL) and mouse
(liver) NKT cells, although the latter detected a substantially
smaller population than CD1d tetramers loaded with ␣-GalCer
(⬃0.3 vs 32%, respectively). Despite this interesting observation clearly identifying PIM as a CD1d ligand, how PIM actually participates in the immune response against mycobacteria is
not yet clear, as it has been shown that CD1d-deficient mice do
not significantly differ in survival from wild-type mice when
infected with M. tuberculosis (83), whereas J␣18 (NKT cell)deficient mice appear to be more susceptible (84). In the context of a Leishmania infection, it was found that lipophosphoglycan (present on the surface of this organism) and related
glycoinositol phospholipids could bind to CD1d and stimulate
IFN-␥ production in a CD1d-dependent manner (85). In that
study, a defective granulomatous response in CD1d-deficient
mice infected with L. donovani was observed, with a concomitant elevation in parasite burden relative to wild-type mice.
Synthetic and nonmicrobial CD1d ligands
It was mentioned above that the ␣-GalCer analog OCH has
been used in autoimmune disease models and that its efficacy in
these models is dependent on a Th2 cytokine “bias” by NKT
cells (51). The predominant NKT cells that are activated by
␣-GalCer, GSL-1, and other microbial glycolipids are the
iNKT cells. Certainly, there could be other CD1d-restricted T
cells that recognize CD1d presenting something other than
these ligands, as is the case for sulfatide, for example (29). In
fact, work from the Moody laboratory has shown that human
noninvariant T cells that are CD1d-restricted can be activated
by ligands that are neither peptides nor lipids. They found that
phenyl pentamethyldihydrobenzofuran sulfonates (PPBFs; Fig.
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diabetes and EAE (reviewed in Ref. 49). As mentioned above,
the activation of NKT cells by ␣-GalCer induces both Th1 and
Th2 cytokines (7). Thus, the idea behind the use of ␣-GalCer in
autoimmune diseases was on the Th2 cytokine side. However,
although multiple injections of ␣-GalCer seem to bias the response toward the production of Th2 cytokines (49), it appears
as though the polarization of NKT cells (i.e., Th1 vs Th2) is
either incomplete or ineffective (50). Interestingly, work by the
Yamamura laboratory tried the approach of an ␣-GalCer analog
in assessing the effect of NKT cell activation on EAE (51). In
this study, the investigators truncated the sphingosine chain essentially in half, generating a molecule called OCH with a truncated sphingosine chain (OCH). It was found that OCH was
substantially greater in its ability to treat and/or prevent the development of EAE than the parental ␣-GalCer. This effect correlated with a higher level of IL-4 production induced by administration of OCH than with ␣-GalCer (51). Other analogs
of ␣-GalCer have been shown to have various effects on NKT
cell activation in vitro, as well as antimicrobial and antitumor
activity in vivo. For example, modifying the acyl chain of the
␣-GalCer molecule KRN 7000 to create a diunsaturated 20 carbon chain results in IL-4 production with a reduction in IFN-␥
secretion (52). The requirements for the binding of this ␣-GalCer analog were less stringent as well, illustrating how changes
in this chain can also have profound effects on NKT cell activation. In contrast to the effects of acyl chain modification on
␣-GalCer activity, Tsuji and colleagues (53–57) used a different approach. In their studies, they used a C-glycosidic form of
␣-GalCer in analyses of the adjuvant properties of ␣-GalCer. It
was found that the C-glycoside induced more of a Th1 (i.e.,
IFN-␥) response, was longer lasting, and was actually a better
adjuvant than the parental compound itself in murine models
of malaria and metastatic melanoma (53–57). Furthermore,
␣-GalCer administration has been shown to be mostly protective activity against viruses (58 – 61), bacteria (62– 67), and
other pathogens (68, 69). In Trypanosoma cruzi, although GPIs
and other lipids from this genus can bind to CD1d, those ligands do not stimulate NKT cells (70). However, although
treatment of mice with ␣-GalCer is protective against infection
with T. cruzi (71), it actually impairs the immune response
against a DNA vaccine specific for this pathogen (72).
Ortaldo and colleagues (73), as well as Parekh et al. (74), have
found that a 12 carbon acyl chain form of galactosylceramide
((␤-GalCer (C12)) can stimulate NKT cells in a CD1d-dependent manner. It has been shown previously that the activation
of NKT cells by ␣-GalCer results in concomitant NK cell stimulation (75, 76). The administration of the ␤-GalCer (C12) in
vivo caused the apparent loss of NKT cells as found with ␣-GalCer (73), but without cytokine expression or activation of NK
cells. Tetramers loaded with ␤-GalCer (C12) could stain NKT
cells, although lower numbers were detected as compared with
when ␣-GalCer-loaded tetramers are used (38 – 40, 73). However, some contamination with minute amounts of ␣-GalCer
cannot be completely ruled out in either of the ␤-GalCer preparations (73, 74). In another study, the s.c. administration of
␤-GalCer (but not ␣-GalCer) to wild-type C57BL/6 mice resulted in a large number of NKT cells infiltrating the site of
injection, similar to the CD1d-independent granulomas induced by the s.c. injection of mycobacterial PI dimannoside
(77). Thus, ␤-GalCer may have some similar yet distinctly different actions on NKT cells.
The Journal of Immunology
3) could stimulate a clonotypic population of human T cells
(V␣2/V␤21 TCR) that were very sensitive to changes in the hydroxylation and methylation patterns at the terminal ends of
these molecules (86). Interestingly, PPBFs did not stimulate
NKT cells, nor did ␣-GalCer stimulate the PPBF-reactive T
cells. The structural relationship of PPBFs with sulfa drugs capable of inducing hypersensitivity reactions in humans may
suggest that some of these responses are CD1d mediated and
that the range of ligands capable of being presented by CD1d is
not limited.
The chicken OVA molecule has been used for analyzing Ag
processing and presentation through “classical” MHC class I
and II molecules. In the context of CD1d, it has been shown
that CTL can be induced in response to OVA in an MHCunrestricted manner, and their cytolytic activity can be inhibited by Abs to CD1d (87).
773
Interestingly, it has recently been shown that PC and phosphatidylethanolamine from plant pollen can stimulate human
CD1d- (and CD1a)-specific T cells (88). The T cells that responded to PC or phosphatidylethanolamine were rather diverse and only rarely included iNKT cells. Of intriguing note, T
cell responses to these pollen phospholipids were mainly observed in allergic patients during pollen season, whereas normal
(nonallergic) subjects rarely displayed such reactivity. This
could also be related (at least to a limited degree) to recent work
by Umetsu and his colleagues (89) in asthma patients.
Final thoughts
It is clear the ligands capable of being presented by CD1d molecules to T cells go well beyond ␣-GalCer and related compounds. Besides its application as a parental compound, ␣-GalCer has quite useful as a “backbone” or “foundation,” as
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FIGURE 3. Pathogen-derived and “other” CD1d ligands. CD1d ligands from Sphingomonas spp., Leishmania donovani, and Mycobacterium tuberculosis, as well
as synthetic PPBF, capable of stimulating various CD1d-restricted T cell subpopulations. LPG, lipophosphoglycan from L. donovani; PIM4, PIM from M. tuberculosis. The number of carbons in the chains indicated as “R” is presented in the illustration next to the respective structures.
774
BRIEF REVIEWS: CD1d LIGANDS—THE GOOD, THE BAD, AND THE UGLY
Acknowledgments
I thank Manjula Nagala, Gourapura Renukaradhya, and Masood Khan for help
with the CD1d ligand structures and comments on the manuscript.
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been given to patients with various forms of cancer in phase I
trials (90 –94). Although none have reported clinical responses,
increased NKT cell activation and cytokine production was evident, suggesting that the potential for antitumor efficacy is
there in more refined future studies. CD1d ligands completely
unrelated to ␣-GalCer have been identified (and perhaps more
of them are to be discovered), as well as the T cell subpopulation(s) stimulated by them. This opens up additional avenues
for investigations aimed at understanding other diseases at a
more basic level, in addition to the translation of those results to
the clinic, where patients present with symptoms of unknown
etiology. As a case in point, it has been shown recently by
Umetsu and colleagues (89) that the majority of CD4⫹ T cells
in the lungs of patients with moderate to severe asthma are, in
fact, iNKT cells. Thus, it is conceivable that natural glycolipid
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GSL-1 (78 – 81), could cause the enhanced number of pulmonary NKT cells in this disease. Certainly, then, the CD1d pathway of Ag presentation has the promise of utility in a number of
different disorders or conditions, and for which we might be
able to exploit their CD1d dependence for novel treatments or
preventative strategies.
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