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Gwen Knapp Center for Lupus and Immunology Research, Committee on Immunology and Department of Pathology, University of Chicago, Chicago, IL 60637;
Immunology Unit, Department of Cell and Molecular Biology, Lund University, Lund, Sweden; and
Division of Rheumatology and Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD1d1 was shown to be the ligand for a unique subset of T cells, the NK
T cells (13). Most of the NK T cells used an invariant 
-chain, with
V14J281 rearrangement, paired with a limited number of
Vß-chains (Vß8, Vß7, or Vß2) (14, 15). Upon activation, NK T
cells rapidly produce significant amounts of cytokines, particularly
IL-4 (16, 17, 18, 19, 20, 21), which may influence the overall dynamics of the immune
response to both infections and autoimmunity. In addition to their
cytokine production ability, a recent study has shown that NK T cells
can mediate tumor rejection through an NK-like effector mechanism after
activation with IL-12 (22). We and others have shown that the
development of NK T cells is impaired in mice lacking either CD1d1
alone (23) or both CD1d1 and CD1d2 (24, 25). These mutant mice are
functionally incapable of producing IL-4 after systemic T cell
activation with anti-CD3 Ab. The induction of other cytokines, such
as IFN-
, was not significantly affected in CD1d1, CD1d2-double
deficient (CD1d1°CD1d2°)3
mice (24, 25), but appeared to be reduced in CD1d1° mice (23). It is
unclear whether this result is due simply to the heterogeneous genetic
backgrounds of mice used in the study, to the different parameters
(mRNA vs protein) used to measure the cytokine induction, or to the
qualitative differences in the remnant population of NK T cells between
CD1d1° and CD1d1°CD1d2° mice.
In this study, we have investigated the expression of CD1d2 in CD1d1° mice and assessed the functional role of CD1d2 by comparing T cell development in CD1d1° and CD1d1°CD1d2° mice. To ascertain whether CD1d2 can act as a restriction element for T cell responses, we also analyzed the reactivity of a panel of CD1-specific T cell hybridomas and T cell clones to CD1d2-expressing cells. Our data demonstrated that the surface expression patterns of CD1d1 and CD1d2 are differentially regulated. In contrast to the broad distribution of mouse CD1d1, CD1d2 surface expression can be detected in substantial quantities only on thymocytes, similar to the pattern found for human CD1a and CD1b (26). Although CD1d2 protein can be recognized by NK T cells, the expression of CD1d2 alone is not sufficient for the development and function of NK T cells in CD1d1° mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A DNA fragment containing the CD1d1 gene was isolated from a 129/sv genomic DNA phage library (Stratagene, La Jolla, CA). The targeting construct was designed to delete a 1.6-kb BamHI fragment containing exons 1 to 3 of the CD1d1 gene and replace these coding regions with the neomycin resistance gene. The linearized targeting construct was transfected into J-1 embryonic stem (ES) cells by electroporation, and G418 and gancyclovir-resistant clones were screened for homologous recombination by Southern blot analysis, using probes both outside and within the target region. ES clones with the mutant CD1d1 gene were injected into C57BL/6 blastocysts. The resulting chimeras were crossed to B6 mice. Mice heterozygous for the mutation were intercrossed to produce homozygous CD1d1° offspring, screened by Southern blot analysis. CD1d1°CD1d2° mice were generated in our laboratory as previously described (25). All animals were housed under specific pathogen-free conditions.
CD1 mRNA expression
RNA was extracted from various tissues of WT, CD1d1°, and CD1d1°CD1d2° mice with TRIzol Reagent (Life Technologies, Grand Island, NY). cDNA was prepared using random hexamer primers and amplified by PCR using primer sets specific for CD1d1 or CD1d2. The sequences of primers were 5'-ACGTCCTGGCAGACAGTCCCAGG-3' and 5'-TTAATGTTGAAAAGAGCGTACTGGC-3' for CD1d1, and 5'-ACATCTTGGCAGAGGGTCCTAGG-3' and 5'-TCCTAAATTTAAAGGAGCATACTGGT-3' for CD1d2. The amount of template cDNA used in each reaction was normalized to the amount of HPRT mRNA amplified with primers 5'-GTTGGATACAGGCCAGACTTTGTTG-3' and 5'-GAGGGTAGGCTGGCCTATAGGCT-3'. The specificity of amplified products was confirmed by Southern blot hybridization using 32P-labeled oligonucleotide probes specific for CD1d1 (5'-ACCTGCCCCCTATTTGTCCG-3') or CD1d2 (5'-ACCTGGCCCCAGTTTGCCCG-3').
Flow cytometric analysis
mAbs specific for CD3 (FITC-2C11), TCRß (FITC-H57-597),
CD8 (FITC-53-6.7), NK1.1 (PE-PK136), CD8ß (PE-53-5.8), CD4
(Cy-chrome-RM4-5), and hamster IgG (FITC-G70-204 and G94-56) were
obtained from PharMingen (San Diego, CA). 3H3, a hamster mAb specific
to CD1, was developed in our laboratory (11). Single cell suspensions
from most tissues of designated mice were prepared by standard
procedures. Lymphocytes from perfused liver were obtained according to
the method described by Goossens et al. (27). Cells were stained using
combinations of fluorescent-conjugated Abs and analyzed with a Becton
Dickinson (San Jose, CA) FACScalibur flow cytometer using
CellQuest software.
Cytokine mRNA analysis
CD1d1°, CD1d1°CD1d2°, and WT controls were injected i.v. with 2 µg of purified anti-CD3 Ab (kindly provided by Dr. Jeffrey Bluestone, University of Chicago), and spleens were removed after 90 min for RNA preparation. RNA extraction and reverse transcription were conducted as described above. Competitive PCR was used to analyze the relative amounts of cytokine mRNA. Briefly, a polycompetitor construct (kindly provided by Dr. Steve Reiner, University of Chicago) containing addition-mutations of authentic cDNA was amplified in the same reaction as the experimental cDNA. The ratio of the larger m.w. products (due to the amplification of the competitors) and the lower m.w. products (due to the amplification of authentic cytokines) was used to assay the relative amount of cytokine mRNA production in vivo. Amplification of HPRT was used to equalize the input cDNA between samples.
Generation of RMA-S and L929 cells stably transfected with CD1d2.
CD1d2 cDNA was obtained by PCR amplification of a B6/CBAF1 thymus cDNA library (Stratagene, La Jolla, CA) with primers 5'-ACGAATTCACCATGCGGTACCTACCATGGCTGTTG-3' (in exon 1) and 5'-CATCCCAGTAGAGGATGATATC-3' (in exon 4). The resulting PCR products were cloned into PCRscript (Stratagene). dsDNA sequencing was performed to identify clones containing the CD1d2 gene. The insert was then shuffled into a pcDNA-3 expression vector (Invitrogen, San Diego, CA) that already contained the DNA sequence encoding the transmembrane, cytoplasmic tail, and 3'-untranslated regions from CD1d1. The resulting chimeric molecule was expected to have an identical amino acid sequence to native CD1d2 molecules since there are no amino acid differences between CD1d1 and CD1d2 beyond exon 4. Twenty micrograms of plasmid DNA were electroporated into RMA-S and L929 cells. Stable transfectants were first selected for G418 resistance, and then for high surface expression of CD1 by staining with the anti-CD1 Ab 3H3.
Activation of T cell hybridomas and NK T cells
Hybridoma cells (5 x 104) were cultured in 200 µl of RPMI 1640 medium (supplemented with 10% FCS, 2 mM L-glutamine, 20 µM 2-ME, and 100 U/ml penicillin/streptomycin) together with irradiated thymocytes or splenocytes (5 x 105 cells per well) or cell lines (5 x 104 cells per well). After 24–48 h, culture supernatants were harvested, and IL-2 release was quantitated by ELISA (PharMingen). CD4+NK1.1+ T cells were purified from the livers of C57BL/6 mice by FACS. Sorted CD4+NK1.1+ T cells (1–2 x 105 cells) were stimulated with irradiated CD1d2-transfected RMA-S cells (5 x 104 cells per well) or parental RMA-S cells in the presence of 10 U/ml of IL-2. After 2 to 3 days, supernatants were collected, and IL-4 levels were determined by ELISA.
Cytotoxicity assay
Target cells (1 x 106 cells) were labeled with 100 µCi [51Cr]sodium chromate for 1 h at 37°C. A total of 1 x 104 cells were added to round-bottom microtiter wells containing variable numbers of effector cells. After 4 h incubation at 37°C, 100 µl of supernatant from each well was assayed for 51Cr release. Results are given as follows: percentage of specific lysis = (experimental - spontaneous release) x 100/(maximal release - spontaneous release).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ES cells lacking a functional CD1d1 gene were
generated by homologous recombination, as outlined in Fig. 1
A. The disruption of the
CD1d1 gene was confirmed by Southern blot analysis. The
targeted embryonic stem cells were used to derive homozygous mice in
which both of the CD1d1 alleles were disrupted (Fig. 1B). The background for both CD1d1° and CD1d1°CD1d2°
mice used in this study was a mixed Sv129/C57BL/6 background.
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Although CD1d1 and CD1d2 are 95%
homologous, we have created two primer sets that specifically amplify
these isotypes based on nucleotide differences in exon three and the 3'
untranslated regions. RT-PCR was used to examine the expression of
CD1d1 and CD1d2 in different tissues from WT and
CD1d1° mice. In WT mice, CD1d1 mRNA can be detected in all
tissues tested, including thymus, spleen, lymph node, liver, and
intestine, with expression highest in liver (Fig. 2A). CD1d2 appears
to be expressed at lower levels than CD1d1, with expression
highest in the thymus and barely detectable in the intestine. In
CD1d1° mice, the CD1d1 mRNA is undetectable, but the
expression pattern of CD1d2 is similar to the WT controls
except that the levels of CD1d2 mRNA are slightly higher in
the thymus and liver of CD1d1° mice. Both CD1d1 and
CD1d2 mRNA are undetectable in CD1d1°CD1d2° mice. The
specificity of amplified products was further confirmed by Southern
blot hybridization with oligonucleotide probes specific to
CD1d1 and CD1d2 respectively (Fig. 2B).
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C). This result suggests that the CD1 expression observed
at the cell surface of splenocytes or lymph node cells is attributable
only to CD1d1, while the CD1 expression on thymocytes can be attributed
to both CD1d1 and CD1d2. Lack of reactivity of 3H3 to the cells
isolated from CD1d1°CD1d2° mice confirms the specificity of this
Ab. Based on the specific mean fluorescence intensity detected by 3H3,
thymocytes from CD1d1° mice were found to express 25–30% of the WT
levels of CD1. CD1d2 does not compensate for the loss of CD1d1 function in NK T cell development
Our previous results and those of Smiley et al. have shown that the development of NK T cells is impaired in CD1d1°CD1d2° mice (24, 25). Mendiratta et al. have also shown that the number of NK T cells was dramatically reduced in the mice lacking only CD1d1 (23). However, it was unclear whether CD1d2 is completely dispensable or whether it can perform at a lower level the same function as CD1d1 in NK T cell development. To address this issue, we compared the development of NK T cells in CD1d1°, CD1d1°CD1d2°, and WT mice by flow cytometry and analyzed their capacity for cytokine production upon primary T cell stimulation.
Lymphocytes from thymus, spleen, lymph node, and liver were stained
with various combinations of fluorochrome-labeled mAbs and detected by
flow cytometry to analyze T cell populations in CD1d1°,
CD1d1°CD1d2°, and WT mice. The number of lymphocytes and the
proportion of CD4+, CD8+,
CD4-CD8-, and
CD4+CD8+ cells did not differ significantly
between groups (data not shown) by staining with anti-TCRß,
anti-CD4, and anti-CD8 Abs. However, the percentages of
NK1+ T cells were reduced by 70–75% in the liver, where
NK1+ T cells are normally prevalent, and 60–75% in other
organs tested in both CD1d1° and CD1d1°CD1d2° mice (Fig. 3A), compared with the control
mice. There was no significant difference in the levels of reduction
between the two knockout mouse lines.
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B).
Both CD1d1° and CD1d1°CD1d2° mice failed to produce a significant
amount of IL-4 mRNA 90 min after injection of anti-CD3 mAb, while
heterozygous littermate controls expressed high levels of IL-4 mRNA at
this time point. The levels of IFN-, IL-2, IL-10, and IL-12 were not
diminished in either CD1d1° or CD1d1°CD1d2° mice compared with
controls. Furthermore, the expression levels of various cytokines in
response to anti-CD3 are comparable in CD1d1° and
CD1d1°CD1d2° mice. We therefore, observe no quantitative or qualitative differences in NK T cell development or function between CD1d1° and CD1d1°CD1d2° mice. Our results suggest that CD1d2 is unable to compensate for the loss of CD1d1 in NK T cell development, despite being expressed on the surface of thymocytes.
The expression of CD1d2 during embryonic development
Several possibilities may account for the inability of CD1d2 to
select NK T cells. One possible explanation is that CD1d2 may not be
expressed during early embryonic development, which could prevent it
from positively selecting NK T cells. We therefore examined cell
surface expression of CD1 on thymocytes of CD1d1° and WT mice during
embryonic development by surface staining with mAb 3H3. As depicted in
Fig. 4, a substantial amount of CD1 can
be detected on cells isolated from day 14.5 fetal thymus from both
CD1d1° and WT mice. The cell surface levels of CD1 remained
relatively constant throughout development in CD1d1° and WT mice,
with cells from CD1d1° mice expressing 25 to 35% of the WT levels of
CD1. The expression of CD1d2 before TCR rearrangement suggests that
CD1d2 could be active in thymic selection of CD1-restricted T cells.
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Although CD1d1 and CD1d2 are highly homologous to each other, they
differ in 17 amino acids in the coding region, including a cysteine
(residue 168) to tryptophan substitution in the 2 domain of CD1d2.
This cysteine participates in disulfide bond formation and is conserved
in most MHC class I molecules. Lack of this intradomain disulfide bond
may cause CD1d2 to adopt a different conformation from that of CD1d1
and may prevent CD1d2 from interacting with NK T cells. To investigate
whether CD1d2 can be recognized by NK T cells, we measured the cytokine
production of NK T cell hybridomas (D32.D3, and DN3A4) in response to
CD1d2-transfected cells and lymphocytes isolated from
CD1d1° and control mice. As shown in Fig. 5A, NK T cell hybridomas
secreted high levels of IL-2 in response to
CD1d2-transfected RMA-S and L929 cells but not in response
to untransfected cells. However, NK T cell hybridomas did not secrete
IL-2 in response to thymocytes from CD1d1° mice, yet secreted
substantial amounts of IL-2 in response to thymocytes from WT controls
(Fig. 5B). Additionally, purified liver NK T cells also can
secrete IL-4 in response to CD1d2-transfected RMA-S cells
(Fig. 5C) but not when stimulated by cells isolated from
CD1d1° mice (data not shown). Thus, our results suggest that,
although the CD1d2 molecule can be recognized by NK T cells, the amount
of CD1d2 expressed on lymphocytes may be too low to trigger the T cell
response.
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In addition to NK T cells, CD1-restricted CD4+,
CD8+, and DN T cells have been isolated (5, 6, 28). Unlike
NK T cells, these CD1-restricted T cells have diverse TCR repertoires.
To analyze the extent of cross-reactivity between CD1d1 and CD1d2, we
also examined the reactivity of the CD1d2 transfectant with
several CD1d1-specific T cell hybridomas (VII49.1, VII68.1, VIII24.1,
and XV19.2) derived from CD4+ splenocytes from MHC II°
mice and CD1d1-specific DN CTLs (14S.7, 14S.10, and 24S.7) from B6 mice
(29). In contrast to the two NK T cell hybridomas, most of the
CD4+ T cell hybridomas respond only to CD1d1transfectants and do not respond to CD1d2 transfectants
(Fig. 5D). Only one CD4+ T cell hybridoma
responded weakly to CD1d2 transfectants (Fig. 5D)
but not to thymocytes from CD1d1° mice (data not shown). The specific
recognition of CD1d2 by CD1d1-specific DN CTLs was determined by the
cytolytic assay. All three CTLs could recognize
CD1d1-transfected RMA-S cells but not untransfected RMA-S
cells, and two of them (14S.7 and 24S.7) also recognized CD1d2transfectant (Fig. 5E). Thus, the amino acid
substitutions in CD1d2 can affect the recognition by some CD1-specific
T cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have investigated several possible explanations that could account for the inefficacy of CD1d2 in the selection and/or expansion of NK T cells. First, we examined the expression of CD1d2 during embryonic development and showed that CD1d2 is already expressed on thymocytes on gestational day 14.5, before TCR rearrangement. This ontogeny eliminates the possibility that lack of expression of CD1d2 during early embryonic development precludes it from functioning as a restriction element for NK T cell development. Second, we examined the reactivity of NK T cells to CD1d2 and found that transfectants expressing high levels of CD1d2 can be recognized both by NK T cell hybridomas and freshly isolated NK T cells. However, these NK T cells cannot secrete cytokines in response to the CD1d2-expressing thymocytes isolated from CD1d1° mice. These results suggested that the epitopes recognized by NK T cells are preserved in the CD1d2 molecule; however, the amount of CD1d2 expressed on thymocytes may not be sufficient to promote the development of NK T cells. Although CD1d2 can be recognized by NK T cells, we do not know whether NK T cells can interact with CD1d2 with the same affinity as with CD1d1. Our FACS analysis showed that the expression level of CD1d1 on thymocytes is 3- to 4-fold higher than that of CD1d2. Therefore, it is likely that the inability of CD1d2 to select NK T cells may result from its low abundance and low affinity for NK T cells. It is also possible that the presence of CD1 molecules in lymphoid organs is essential for the expansion of NK T cells and that lack of expression of CD1d2 in peripheral lymphoid organs precludes the expansion and functional development of NK T cells. If this were the case, we would expect that the development of NK T cells would be partially restored in the thymus of CD1d1° mice. However, both surface phenotype analysis and in vitro cytokine secretion ability of thymocytes in response to plate-bound anti-CD3 (data not shown) showed lack of functional NK T cells in the thymus of CD1d1° mice.
The expression pattern of CD1d2 appears to be controlled at the transcriptional level since the surface expression level of CD1d2 is consistent with its mRNA expression level. To elucidate the mechanisms regulating the expression of the murine CD1 genes, we have cloned and sequenced the 5' flanking region of the murine CD1d1 and CD1d2 genes (Y.-H. Chen and C.-R. Wang, unpublished results). CD1d1 and CD1d2 share greater than 95% sequence homology in the coding exons and intervening introns. The homology extends about 350 bp 5' of the translational start site with marked upstream divergence. There is an L1 repeat in the upstream region of CD1d2, which may explain the lower expression of CD1d2 relative to CD1d1.
Of the 17 amino acid changes between CD1d1 and CD1d2, 16 substitutions
occurred in the 1 and 2 domains (Fig. 6). Six of these substituted amino acids
extend into the Ag-binding groove, which might affect Ag binding. If
the binding mode of CD1 with the TCR is similar to that between other
MHC molecules and their receptors (32, 33), then two substituted
residues (162M
T and 170LQ)
protruding up out of the groove might affect the interaction
with the V-chain of the TCR. Nine CD1d1-specific T cell hybridomas
or T cell lines, including two NK T cell hybridomas, four
CD4+ T cell hybridomas, and three DN cytotoxic T cell
clones, were tested for their reactivity with CD1d2 in this study.
Three of these T cells (D32.D3, DN3A4, and 24S.7) use a V-chain with
V14J281 rearrangement, while the other six use different
V-chains. Four of these T cells lines showed differential
recognition of CD1d1 vs CD1d2, suggesting that the structural
differences between CD1d1 and CD1d2 can be distinguished by some T
cells. It is worth mentioning that all three V14J281-expressing T
cells reacted with both CD1d1 and CD1d2. Thus, it is likely that the
epitopes recognized by the invariant TCR -chain of NK+ T
or NK- T cells are preserved in CD1d2 but that the
epitopes recognized by heterogenous TCR used by other subsets of
CD1-autoreactive T cells may be mostly unique to CD1d1.
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B), and three of four
spleen-derived hybridomas secreted more IL-2 when stimulated with
splenocytes than with thymocytes (data not shown). Although our results
showed that the responses to CD1d2 by these CD1-specific T cells are
heterogeneous, it is unlikely that the differential ability of these T
cells to recognize CD1d2 would be the explanation for tissue-specific
CD1-recognition since CD1d2 is not expressed on splenocytes. It is more
likely that CD1-specific autoreactive T cells can distinguish a set of
cell type-specific ligands bound to CD1, as suggested by Brossay et al.
(34) and Park et al. (35). The CD1d2 gene is present in all mice strains studied so far, including many inbred strains, and in wild mice of the subspecies castaneus and spretus (B. Wang et al., unpublished results). However, rats have only one CD1 gene, which appears to be related more to CD1d1 than to CD1d2 (36). Thus, the gene duplication event of mouse CD1 occurred less than 10 million years ago. Has CD1d2 acquired a unique function in the mouse or is it simply a by-product of gene duplication that will eventually become a pseudogene by accumulating mutations in both the coding and promoter regions? Although CD1d2 cannot substitute for CD1d1 in positive selection of NK T cells, we cannot eliminate the potential role of CD1d2 in shaping the repertoire of other CD1-restricted T cells. The fact that CD1d2 is capable of encoding a functional protein and being recognized by NK T cells and other autoreactive CD1-specific T cells raises the possibility that induced expression of CD1d2 in the periphery may lead to activation of some CD1-specific T cells. Control of the tissue distribution and expression level of CD1d2 may therefore be necessary in the mouse to prevent autoimmune responses.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to: Dr. Chyung-Ru Wang, Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, 924 East 57th Street, Chicago, IL 60637-5420. E-mail address:
3 Abbreviations used in this paper: CD1d1°CD1d2°, CD1d1, CD1d2-double deficient; CD1d1°, CD1d1-deficient; HPRT, hypoxanthine phosphoribosyltransferase; ES, embryonic stem; WT, wild type, PE, phycoerythrin; DN, double negative.
Received for publication October 7, 1998. Accepted for publication January 13, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß+ T cells. Nature 372:691.[Medline]
14 NK T cells by glycosylceramides. Science 278:1626. chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4-8- T cells in mice and humans. J. Exp. Med. 180:1097./ß T cell receptors expressed by the B2A2 (J11d)-subset of CD4-8- thymocytes. Eur. J. Immunol. 19:25.[Medline]
ß- T cell receptor+ CD4- CD8- T cells produce IL-4. J. Immunol. 149:1211.[Abstract]
14 NK T cells in IL-12-mediated rejection of tumors. Science 278:1623.ß T cell receptor structure at 2.5Å and its orientation in the TCR-MHC complex. Science 274:209.This article has been cited by other articles:
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  F. C. M. Sille, M. Boxem, D. Sprengers, N. Veerapen, G. Besra, and M. Boes Distinct Requirements for CD1d Intracellular Transport for Development of V{alpha}14 iNKT Cells J. Immunol., August 1, 2009; 183(3): 1780 - 1788. [Abstract] [Full Text] [PDF]
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Y. Geng, P. Laslo, K. Barton, and C.-R. Wang Transcriptional Regulation of CD1D1 by Ets Family Transcription Factors J. Immunol., July 15, 2005; 175(2): 1022 - 1029. [Abstract] [Full Text] [PDF]
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H. Xu, T. Chun, A. Colmone, H. Nguyen, and C.-R. Wang Expression of CD1d Under the Control of a MHC Class Ia Promoter Skews the Development of NKT Cells, But Not CD8+ T Cells J. Immunol., October 15, 2003; 171(8): 4105 - 4112. [Abstract] [Full Text] [PDF]
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M. Cernadas, M. Sugita, N. van der Wel, X. Cao, J. E. Gumperz, S. Maltsev, G. S. Besra, S. M. Behar, P. J. Peters, and M. B. Brenner Lysosomal Localization of Murine CD1d Mediated by AP-3 Is Necessary for NK T Cell Development J. Immunol., October 15, 2003; 171(8): 4149 - 4155. [Abstract] [Full Text] [PDF]
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V. Sriram, S. Cho, P. Li, P. W. O'Donnell, C. Dunn, K. Hayakawa, J. S. Blum, and R. R. Brutkiewicz Inhibition of glycolipid shedding rescues recognition of a CD1+ T cell lymphoma by natural killer T (NKT) cells PNAS, June 11, 2002; 99(12): 8197 - 8202. [Abstract] [Full Text] [PDF]
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T. J. Roberts, V. Sriram, P. M. Spence, M. Gui, K. Hayakawa, I. Bacik, J. R. Bennink, J. W. Yewdell, and R. R. Brutkiewicz Recycling CD1d1 Molecules Present Endogenous Antigens Processed in an Endocytic Compartment to NKT Cells J. Immunol., June 1, 2002; 168(11): 5409 - 5414. [Abstract] [Full Text] [PDF]
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B. Wang, T. Chun, I. C. Rulifson, M. Exley, S. P. Balk, and C.-R. Wang Human CD1d Functions as a Transplantation Antigen and a Restriction Element in Mice J. Immunol., March 15, 2001; 166(6): 3829 - 3836. [Abstract] [Full Text] [PDF]
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A. Molano, S.-H. Park, Y.-H. Chiu, S. Nosseir, A. Bendelac, and M. Tsuji Cutting Edge: The IgG Response to the Circumsporozoite Protein Is MHC Class II-Dependent and CD1d-Independent: Exploring the Role of GPIs in NK T Cell Activation and Antimalarial Responses J. Immunol., May 15, 2000; 164(10): 5005 - 5009. [Abstract] [Full Text] [PDF]
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B. Wang, T. Chun, and C.-R. Wang Comparative Contribution of CD1 on the Development of CD4+ and CD8+ T Cell Compartments J. Immunol., January 15, 2000; 164(2): 739 - 745. [Abstract] [Full Text] [PDF]
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), RMA-S CD1d1 (•), or
RMA-S CD1d2 (
). The E:T ratios were indicated in the figure.