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Requirements for CD1d Recognition by Human Invariant V24⁺ CD4^–CD8^– T Cells

Mark Exley^*, Jorge Garcia^*, Steven P. Balk^*, and Steven Porcelli

From the ^* Cancer Biology Program, Hematology/Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215; and Lymphocyte Biology Section, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

	Abstract

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A subset of human CD4^–CD8^– T cells that expresses an invariant V24-JQ T cell receptor (TCR)- chain, paired predominantly with Vβ11, has been identified. A series of these V24 Vβ11 clones were shown to have TCR-β CDR3 diversity and express the natural killer (NK) locus–encoded C-type lectins NKR-P1A, CD94, and CD69. However, in contrast to NK cells, they did not express killer inhibitory receptors, CD16, CD56, or CD57. All invariant V24⁺ clones recognized the MHC class I–like CD16 molecule and discriminated between CD1d and other closely related human CD1 proteins, indicating that recognition was TCR-mediated. Recognition was not dependent upon an endosomal targeting motif in the cytoplasmic tail of CD1d. Upon activation by anti-CD3 or CD1d, the clones produced both Th1 and Th2 cytokines. These results demonstrate that human invariant V24⁺ CD4^–CD8^– T cells, and presumably the homologous murine NK1⁺ T cell population, are CD1d reactive and functionally distinct from NK cells. The conservation of this cell population and of the CD1d ligand across species indicates an important immunological function.

The CD1 locus encodes a family of conserved nonpolymorphic proteins structurally related to MHC class I and II proteins (1–5). Human and murine CD1-restricted T cell lines and clones that recognize lipid antigens (6–8) or hydrophobic peptide antigens (9) have been identified, indicating that CD1 proteins can function as specialized antigen-presenting molecules. A distinct function for murine CD1d appears to be as a ligand or antigen-presenting molecule recognized by a population of T cells that express the NKR-P1C (NK1) cell surface C-type lectin (10–14). NK1 is otherwise restricted to NK cells and these NK1⁺ T cells have also been referred to as NK T cells or natural T cells (15, 16). Phenotypically, these cells are either CD4⁺CD8^– or CD4^–CD8^– (double negative, DN¹), and forced expression of CD8 in transgenic mice results in the deletion of this population (12, 17). Most strikingly, the majority of these cells use an invariant TCR- chain (V14-J281) that pairs preferentially with Vβ8, 7 or 2 (17–20). NK1⁺ T cells appear to play a role in regulating immune responses, based upon their ability to rapidly produce large amounts of IL-4 after stimulation with anti-CD3 in vivo (21–24). However, these cells also produce large amounts of IFN-, and production of this cytokine can be specifically induced by stimulation through NK1 (25). The immunological functions of these cells and the physiologically relevant CD1d-presenting cells mediating their activation remain to be determined.

Analyses of the CD1 genes in humans and other species indicate that the proteins fall into two groups, CD1a-, b-, and c-like (group 1), and CD1d-like (group 2) (3, 26). The murine CD1 locus appears unique in that it has deleted the group 1 genes, and contains only a duplicated group 2 gene (27, 28). This observation suggests that there may be important functional differences between the CD1 proteins in mice and other species. Nonetheless, a human invariant TCR- chain closely related to the murine invariant V14-J281 TCR has been identified as a predominant TCR used by TCR-/β DN T cells from multiple normal donors (29). This human invariant TCR- is generated by a rearrangement between V24 (TCRAV24) and JQ with no N-region diversity. Subsequent studies have shown that the human invariant V24-JQ TCR- chain associates preferentially with Vβ11 (TCRBV11) (30–32), which is homologous to murine Vβ8. This invariant TCR may also be expressed by a small proportion of CD4⁺ T cells, but not CD8⁺ T cells (31). These observations suggest that human invariant V24⁺ T cells are homologous to murine NK1⁺ T cells.

To better understand the function of these cells and their requirements for specific activation, a series of human invariant V24⁺Vβ11⁺ DN T cell clones were established and characterized. TCR-β sequence analysis demonstrated that these cells were derived from a polyclonal population with no evidence of a shared β chain CDR3 motif. Phenotypically, the clones expressed high levels of NKR-P1A, the only known human homologue of rodent NK1 (33). They also expressed CD94 and CD69, two other C-type lectins closely linked to NKR-P1A in a chromosomal region referred to as the NK locus. However, these cells did not express the NK cell-associated p58 or p70 HLA class I killer cell inhibitory receptors (KIRs; 34, 35) or other markers of NK cells including CD16, CD56, or CD57. Upon stimulation, the clones secreted cytokines associated with both Th1 and Th2 cells, including IFN- and IL-4, respectively. Of the four characterized human CD1 proteins, each clone specifically recognized only CD1d expressed on human or hamster cell transfectants. CD1d recognition was not dependent upon the specific TCR-β chain CDR3 sequence. Moreover, deletion of an endosomal targeting sequence motif in the cytoplasmic tail of CD1d (4, 5, 36) did not effect recognition, suggesting that recognition by these cells was not dependent upon efficient targeting of CD1d to a specialized endosomal compartment involved in antigen processing. These results demonstrate that human invariant V24⁺Vβ11⁺ DN T cells are a specialized population of CD1d-specific T cells. The results also indicate that the similarities between this T cell population, and presumably the homologous murine NK1⁺ T cell population, to NK cells may be limited to the expression of certain closely linked NK locus–encoded C-type lectins.

	Materials and Methods

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Cell Lines and Clones.
T cell lines and clones were derived and phenotypic analyses performed essentially as described (32). In brief, DN V24⁺Vβ11⁺ human peripheral blood T cell lines and clones were established by sequential negative (CD4CD8) and positive (V24Vβ11) magnetic bead and FACS^® sorting, respectively, of human peripheral blood T cells followed by stimulation with PHA-P (reconstituted according to the supplier's instructions and used at a final dilution of 1:2,000; Difco, Detroit, MI) and IL-2 (1.5 nM; Ajinomoto, Yokohama, Japan) in the presence of irradiated (5,000 rads) peripheral blood mononuclear cell feeders. Clones were established by limiting dilution. Clones and lines were maintained by restimulation every 3–6 wk as above with phenotype monitored by FACS^®. A human IL-2–dependent NK cell line, NKL, (37) was provided by Drs. M. Robertson (Indiana University Medical Center, Indianapolis, IN) and J. Ritz (Dana Farber Cancer Institute, Boston, MA).

Antibodies and Phenotypic Analyses of T Cells.
The following antibodies were obtained from the fifth Leukocyte Workshop unless otherwise indicated: anti-V24 (C15B2) and anti-Vβ11 (C21D2) (provided by Dr. A. Lanzavecchia [Basel Institute for Immunology, Basel, Switzerland]); anti–TCR-/β (BMA031; provided by Dr. R.G. Kurrle, Boehringwerke, Marburg, Germany); anti-CD3 (SPV-T3b and OKT3; provided by Dr. H. Spits [Netherlands Cancer Center, Amsterdam, Netherlands] and American Type Culture Collection [Rockville, MD], respectively); anti-CD4 (OKT4; American Type Culture Collection); anti-CD8 (OKT8; American Type Culture Collection); anti-CD8β (2ST8.5H7; from Dr. E. Reinherz [Dana Farber Cancer Institute]); anti-CD16 (ABA2B1); anti-CD28 (9.3); anti-CD56 (MEM188, MOC-1, 0218); anti-CD57 (TB01, TB02); anti-CD69 (PharMingen, San Diego, CA); anti-CD94 (HP-3D9; PharMingen); anti-NKR-P1A (DX1 and DX12, provided by Dr. L. Lanier (DNAX, Palo Alto, CA); HP-3G10 and 191B8); anti-p58 KIR (NK workshop mAbs GL183, EB6, CH-L, and HP-3E4); and anti-p70 KIR (DX9; provided by Dr. L. Lanier). Isotype control mAbs were P3 (IgG₁), 4A7.6 (IgG_2a, provided by Dr. D. Olive [Institut National de la Sante et de la Recherche Medicale, Marseille, France]), and MPC11 (IgG_2b).

CD1d-specific mAbs were raised from mice immunized with CD1d–IgG fusion proteins. Further characterization of these CD1d proteins and antibodies will be reported (Balk, S., and S. Porcelli, manuscript in preparation). CD1d mAbs were purified from low IgG serum (GIBCO BRL, Gaithersburg, MD) containing tissue culture medium by protein G (Pharmacia, Piscataway, NJ) chromatography. FACS^® analysis was by indirect immunofluorescence as described (32). Positive controls included an NK cell line as above and other cell lines and clones derived from peripheral blood. TCR transcripts were amplified by reverse transcriptase (RT)-PCR using variable and constant region-specific primers as described previously (29, 38). Sequences were determined directly from the PCR products on an automated DNA sequencer (ABI 373A).

CD1 Transfectants.
Chinese hamster ovary (CHO) and C1R cells were transfected with a CD1d cDNA (3) in the pSR-neo expression vector (39), followed by G418 selection and FACS^® to generate lines stably expressing CD1d. C1R cells stably transfected with CD1a, b, and c in the pSR-neo vector were described previously (38). The CD1d-CD1a chimeric protein was generated using an Xba1 restriction site located at the 3' end of the 3 domain in CD1a and CD1d. The C1R line established with this chimera construct in the pSR-neo vector was uniformly CD1d positive after G418 selection and was used in these experiments without further enrichment for CD1d⁺ cells.

Functional Analysis of T Cells.
T cell activation for cytokine analysis was done using 10⁵ T cells/well in 96-well flat-bottomed plates coated with anti-CD3 at 10 µg/ml for 48 h. Stimulation with CD1 was done using equal numbers of T cells and stimulator cells (10⁵/well) for 48 h, unless otherwise indicated. For CHO cells, a 30-s glutaraldehyde fixation (0.05% in PBS) was used to bypass the need for costimulatory molecules (40). For stimulation by CHO and C1R transfectants, PMA was included at 1 ng/ml, except where stated otherwise. PHA control stimulations were carried out using a 2,000-fold dilution as described above. For antibody blocking experiments, CD1d transfectants were mixed with mAb dilutions immediately before addition of T cells.

Released cytokine levels were determined by ELISA with matched antibody pairs in relation to cytokine standards. The antibodies for IFN- were from Endogen, Inc. (Boston, MA) and the others were from PharMingen. T cell proliferation was determined by incorporation of [³H]thymidine (0.5 mCi/well) using glutaraldehyde fixed (0.05%) or irradiated (5,000 rads) stimulator cells where indicated. Results shown are means of triplicate samples with error bars representing standard deviations.

	Results

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Isolation and TCR Analysis of Invariant V24-JQ DN T Cells.
Circulating DN T cells were isolated from the peripheral blood of two healthy donors (DN1 and DN2) by anti-CD4 and -CD8 depletion (29, 32). DN V24⁺ T cells were then positively selected from these populations using the C15B12 mAb, specific for V24 (41), and clones were established by limiting dilution. V24⁺ T cell lines from these populations were also established by bulk stimulation with PHA, and the majority of the cells in these lines (75– 95%) were found to be Vβ11⁺ using the C21D2 mAb (31). DN and single positive T cells from a third healthy donor (DN3 and SP3, respectively) were isolated by positive selection with the V24 and Vβ11 mAbs and cloned by limiting dilution. As reported previously, the majority of these latter clones were CD4⁺, but only the DN clones from this donor expressed JQ (32).

The TCR structure of a series of eight DN V24⁺ Vβ11⁺ clones from donor 2 and single clones from donors 1 and 3 was analyzed. Sequence analysis demonstrated that the DN clones from donors 1 and 3 and all but one of the clones from donor 2 expressed the invariant V24 TCR- chain (Table 1). Significantly, in one invariant V24⁺ clone (DN2.C7), the V24-encoded serine was apparently removed during recombination and the serine was regenerated through an N-region addition and recombination 2 bp further 5' in JQ (Fig. 1). These results confirmed the high frequency of the invariant V24 TCR among DN V24⁺ T cells, and suggested that this TCR is strongly selected based upon its protein structure, rather than being generated exclusively by a developmentally programmed precise joining of V24 and JQ gene segments.

View this table: [in this window] [in a new window]   Table 1 CDR3 Sequences of V24+Vβ11+ Clones

 

View larger version (6K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Invariant V24+ TCR- nucleotide and derived amino acid sequences. DN invariant V24+ T cell clone cDNA was sequenced. One clone (DN2.C7) had a distinct nucleotide sequence, which resulted in an identical amino acid sequence as shown.

 
In contrast to the invariant TCR- structure of the DN V24⁺Vβ11⁺ clones, multiple distinct TCR-β sequences were identified (Table 1). The TCR-β sequences from a series of CD4⁺, V24⁺Vβ11⁺ clones that did not use the invariant V24 were also determined for comparison. The identification of multiple Vβ sequences in the clones from donor 2 demonstrated that the DN invariant V24⁺ population may be derived from a large number of independent clones in single donors. The TCR-β chains were also noteworthy for their markedly diverse CDR3 structures and Jβ usage. There was no suggestion of a common CDR3 sequence motif, and even CDR3 length was quite variable. This TCR-β diversity raised the possibility that these clones might recognize diverse antigens in spite of their invariant TCR- chain. Alternatively, the lack of conserved TCR-β chain structure may indicate that the TCR-β CDR3 did not contribute significantly to recognition by the TCRs of these cells.

Expression of Cell Surface Proteins Associated with NK Cells.
The relationship between invariant V24⁺ DN T cells and NK cells was explored using a panel of mAbs recognizing proteins expressed predominantly by NK cells. Humans appear to have only a single NK1-like gene, the homologue of murine NKR-P1A, that is expressed by NK cells and, at low levels, by a subpopulation of peripheral blood T cells (33). Nonetheless, NKR-P1A was expressed at high levels by each of the invariant V24⁺ clones (Table 2 and Fig. 2), but not by any of the CD4⁺ V24⁺Vβ11⁺ clones that did not express the invariant V24-JQ rearrangement (data not shown).

View this table: [in this window] [in a new window]   Table 2 Expression of NK-associated Proteins by Invariant V24+ T Cells

 

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Expression of NK-associated proteins by invariant V24+ T cells. FACS® profiles of a representative DN invariant V24+ T cell clone (DN2.C9) 4 wk after PHA stimulation. T cells were stained with mAbs against the antigens shown or isotype-matched control mAb at 10 µg/ml and with anti-IgG FITC conjugate for 30 min each before FACS® analysis with propidium iodide gating on viable cells. (Top, left to right) P3 isotype control (open histogram) and V24 (solid histogram), NKR-P1A, CD69, CD94. (Bottom, left to right) p58 KIR (GL183 shown), CD16, CD56, CD57.

 
CD69, CD94, and the NKG2 family are additional C-type lectins linked to NKR-P1A in the human NK locus. CD69 is an early and transient T cell activation marker (42), but expression of CD69 by each of the invariant V24⁺ clones persisted at high levels for long periods (>3 wk) after in vitro stimulations (Table 2 and Fig. 2). CD94, a possible NK cell receptor for class I proteins (43–46), was also expressed at high levels by all of the invariant V24⁺ clones. In contrast, prolonged high level expression of these NK locus–encoded proteins was not observed on any of a series of similarly derived CD4⁺ clones or on more than a very small fraction of PHA-stimulated PBLs (data not shown). Cell surface expression of the NKG2 family (47), members of which may associate with CD94 (48), could not be assessed as there are no NKG2-specific, surface-reactive NKG2 antibodies readily available (Bach, F., and J. Houchins, personal communications).

In contrast to the NK locus–encoded C-type lectins, other functionally important receptors expressed by NK cells, but encoded at other genetic loci, were not expressed at significant levels by the invariant V24⁺ clones. These included the p58 and p70 HLA class I–specific KIRs, CD16, CD56, and CD57 (Table 2 and Fig. 2). Finally, each clone expressed low and variable levels of CD28 and CD8, but not CD8β. CD8 was similarly detected at low levels on some cells from the CD4⁺ V24⁺ invariant V24^– clones (Table 2 and data not shown), consistent with its appearance as a late activation antigen. Taken together, these results further supported the conclusion that human invariant V24⁺ T cells and murine invariant V14-J281 NK1⁺ T cells are homologous. However, the relationship of these cells to classical NK cells appeared limited to their expression of NK locus genes, but not of genes encoded elsewhere that are characteristically expressed by NK cells.

Effector Functions of Invariant V24 T Cells.
Cytokine production by the series of invariant V24Vβ11 clones in response to stimulation by plate-bound anti-CD3 was assessed. For comparison, a series of CD4⁺ V24⁺-JQ^– Vβ11⁺ clones was also analyzed and IL-4/IFN- ratios compared (Table 3). With the exception of DN2.D7, the invariant V24⁺ clones all produced substantial levels of IFN- and IL-4, associated with Th1 and Th2 T cells, respectively. Compared to the CD4⁺ clones, there was a trend towards higher levels of IL-4 production by the invariant V24⁺ clones, whether assessed based upon absolute IL-4 production or IL-4/IFN- ratios. This contrasts, to some extent, with an apparent bias in humans towards the generation of T cells that produce much higher levels of IFN- relative to IL-4 (Th1 type cells) in the absence of polarizing stimuli (49, 50). However, there was overlap between the invariant V24⁺ DN clones and the CD4⁺ clones with respect to IL-4 and IFN- production, and IL-4/IFN- ratio, indicating that the invariant V24⁺ DN T cells had a phenotype that did not fall clearly into the Th1 or Th2 categories. The DN clones also produced IL-13, and some produced IL-10 at levels that were not clearly distinct from the CD4⁺ cells.

View this table: [in this window] [in a new window]   Table 3 Cytokine Responses of Invariant TCR+ T Cells to Mitogenic Stimulus

 
Recognition of CD1d-transfected CHO Cells by DN Invariant V24⁺ Clones.
CD1d recognition was assessed initially using CD1d-transfected CHO cells. Each of the five invariant V24⁺ clones assayed responded specifically to the CD1d-transfected CHO cells based upon T cell proliferation (not shown) and cytokine release (Fig. 3). Recognition of CD1d required PMA and mild aldehyde fixation of the target cells, which have been shown in other systems to substitute for certain physiological costimulatory signals (40). Fig. 3 a shows that the CD1d transfectants stimulated IL-4 production from each of the clones except DN2.C9, with the highest levels produced by DN2.B9 and DN2.D6. The CD1d transfectants also strongly stimulated IFN- production from three of these clones (DN2.B9, DN2.C9, and DN2.D6) and modest, but specific, IFN- release by the other two clones (Fig. 3 b). In contrast, the invariant V24^– clones did not respond specifically to the CD1d transfectants (Fig. 3, a and b, and data not shown). The failure of the DN2.C9 clone to produce significant IL-4 in response to the CD1d transfectant was consistent with the relatively low ratio of IL-4/IFN- produced by this clone in response to anti-CD3 stimulation (Table 3). Indeed, the relative levels of IL-4 and IFN- release in response to CD1d from each of the clones were comparable to those observed with anti-CD3 (Table 3).

View larger version (32K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Invariant V24+ T cells responded to CD1d CHO transfectants specifically. DN invariant V24+ T cell clones (DN2.B9, C6, C7, C9, and D6) and control CD4+ V24+ invariant TCR-negative T cell clones (SP3.4G9 and 5B2), all at 2 x 105/well were stimulated with 0.05% glutaraldehyde-fixed CD1d+ CHO transfectants or control CHO cells (2 x 105/ well). PMA (1 ng/ml) and IL-2 (1 nM) were included, and secreted IL-4 and IFN- measured at 48 h by ELISA in triplicate (standard deviations shown). Similar results were obtained without IL-2. (a) IL-4; (b) IFN-.

 
Antibody inhibition studies were performed to confirm that CD1d was recognized and to rule out the possibility that peptide fragments of CD1d were the actual target of the invariant V24⁺ clones. Two mAbs that recognized native CD1d protein (42.1 and 51.1) could almost completely block activation of the DN2.D6 T cell clone at concentrations 0.2 µg/ml (Fig. 4 and data not shown). A third anti-CD1d mAb (68.2) partially blocked, but only at higher concentrations. Several isotype-matched control antibodies used for blocking had no significant effect. Directly comparable results were seen with the second clone analyzed (DN2.D5; data not shown).

View larger version (9K): [in this window] [in a new window] [Download PPT slide]   Figure 4 CD1d antibodies inhibited invariant V24+ T cell recognition of targets. DN invariant V24+ T cell clone DN2.D5 (105/well) was stimulated with fixed CD1d+ CHO cell transfectants (105/well) as in Fig. 3. Control and CD1d-specific mAb were included at 0.67 µg/ml, and secreted IFN- measured by ELISA. Higher concentrations of mAb gave similar results except for 68.2, where inhibition was more complete.

 
Recognition of CD1d-expressing B Cell Transfectants.
Stimulation of invariant V24⁺ T cells by CD1d⁺ CHO cells required both PMA and aldehyde fixation, presumably due to the absence of necessary costimulatory ligands on the CHO cells. Although the target cells that mediate activation of invariant V24⁺ T cells in vivo are not known, normal B cells express CD1d (51) and may be a relevant CD1d-presenting cell. Therefore, the C1R HLA-A and -B negative B lymphoblastoid cell line (52), which does not express detectable CD1d (our unpublished data), was used to confirm the results in CHO cells and to determine whether the need for nonphysiological costimulation could be reduced or eliminated. CD1d-transfected C1R cells specifically stimulated each of the invariant V24⁺ DN T cell clones tested based upon IFN- and IL-4 production and T cell proliferation (Fig. 5 a and data not shown), confirming the results in CHO cells. Stimulation did not require aldehyde fixation, but phorbol ester was still necessary.

View larger version (30K): [in this window] [in a new window] [Download PPT slide]   Figure 5 Invariant V24+ T cells responded to CD1d B cell transfectants. T cell clones (105/ well) were incubated for 48 h with either fixed (0.025 or 0.05% glutaraldehyde, latter shown) or unfixed C1R human B cells (105/well) transfected with CD1a, b, c, d, or plasmid alone. Results with the two fixations were indistinguishable. PMA (1 ng/ml) was included and PHA as positive control is shown for comparison. Representative IFN- cytokine ELISA results of multiple experiments are shown. (a) Production of IFN- by DN2.C9 incubated for 48 h with C1R ± fixation. (b) IFN- cytokine responses of three representative DN2 T cell clones incubated for 48 h with unfixed C1R transfected with CD1a, b, c, d, mock, or mock with PHA.

 
The fine specificity of CD1d recognition was further assessed using C1R cells stably transfected with CD1a, b, or c versus CD1d. The CD1a, b, and c transfectants were not significantly more active than the mock transfectant in stimulating IFN- (Fig. 5 b) or IL-4 production (not shown) from any of the clones examined, although they were able to stimulate CD1a–, b–, or c–reactive T cell clones, respectively (6, 53). In marked contrast, the CD1d C1R transfectants stimulated the production of IFN- (Fig. 5 b) and IL-4 (not shown) at levels directly comparable to those produced in response to PHA.

CD1d Recognition by Invariant V24⁺ T Cells Not Expressing Vβ11.
Polyclonal DN T cell lines selected for expression of V24 were sorted into Vβ11⁺ or Vβ11^– populations and examined to determine whether Vβ11 was necessary for CD1d recognition. FACS^® analyses showed that virtually all of the cells in both lines were V24⁺ (Fig. 6 a), and previous RT-PCR analyses of these lines showed that both expressed primarily or exclusively the invariant V24 (32). The line designated as DN2.Vβ11^– had no significant Vβ11⁺ population, whereas the line designated as DN2.Vβ11⁺ was virtually all Vβ11⁺ (Fig. 6 a). It is of interest that cells in the Vβ11^– line consistently expressed slightly lower TCR levels, based upon staining with the anti-V24 mAb (Fig. 6 a) and anti-TCR mAbs (not shown). The relationship of this observation to the preferential use of Vβ11 by invariant V24⁺ T cells is not clear, but could reflect greater stability of the invariant V24 when paired with Vβ11.

View larger version (23K): [in this window] [in a new window] [Download PPT slide]   Figure 6 Invariant V24+ T cells that did not express Vβ11 responded to CD1d. (a) Representative FACS® profiles of two DN invariant TCR+ T cell lines (DN2.Vβ11+, left; and DN2.Vβ11–, right). T cells were stained with 10 µg/ml of mAbs against V24, Vβ11, or isotype control mAb and with anti-IgG FITC conjugate for 30 min each before FACS® analysis of viable cells. (b) T cell lines (105/well) were incubated with unfixed C1R human B cells (105/well) transfected with CD1a, b, c, d, mock, or mock with PHA as in Fig. 5 and IFN- production results are shown.

 
CD1 recognition by cells in both lines was compared using the panel of CD1-transfected C1R cells. Both the Vβ11⁺ and Vβ11^– lines were activated specifically by the CD1d-transfected C1R cells (Fig. 6 b). Although the response by the Vβ11^– line was quantitatively less, the responses by both lines were comparable to the corresponding PHA responses and most likely represented maximal activation for each line. These results demonstrated that T cells expressing the invariant V24 TCR- paired with Vβs other than Vβ11 can mediate CD1d recognition.

Contribution of the CD1d Endoplasmic Targeting Motif to Recognition.
Human CD1b, c, d, and murine CD1d, but not human CD1a, have short cytoplasmic tails containing a sequence motif, Tyr-X-X-Z (where X is any amino acid and Z is a hydrophobic amino acid), shown to regulate the intracellular trafficking of many transmembrane proteins (54). Previous studies demonstrated a critical role for this motif in the endosomal localization of human CD1b (36). To determine whether this sequence is necessary for the cell surface expression and function of CD1d, the transmembrane domain and cytoplasmic tail from CD1a was fused to the CD1d ectodomain. A C1R cell line transfected with this CD1d-CD1a chimera expressed moderate levels of CD1d at the cell surface (Fig. 7 a). The level of CD1d expression was lower than in the C1R line expressing wild-type CD1d, as this latter line was initially sorted for CD1d⁺ cells.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Figure 7 Invariant V24+ T cells responded to chimeric CD1d with intracellular CD1a. (a) FACS® profiles of C1R CD1d (left) and CD1d/a chimera (right) transfectants stained with normal mouse serum (open histogram) or 42.1 CD1d-specific mAb (solid histogram). (b) DN2.D6 T cell clone (105/well) was incubated with unfixed C1R human B cell CD1d/a chimera or mock transfectants (105/well) and IFN- cytokine ELISA results obtained.

 
Despite lower levels of CD1d expression, the C1R cells expressing the CD1d-CD1a chimeric protein were very effective at activating invariant V24⁺ clones. The DN2.D5 clone produced both IFN- (Fig. 7 b) and IL-4 (not shown) in response to the chimeric protein at levels comparable to those induced by PHA stimulation. Identical results were seen with a second clone, DN2.D6 (not shown). Therefore, deletion of the targeting motif did not impair CD1d recognition by invariant V24⁺ DN T cells.

	Discussion

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This report demonstrated the expression of invariant V24⁺ TCRs by a distinct population of CD1d-reactive DN T cells that appear to be closely related, both phenotypically and functionally, to murine NK1⁺ T cells. A series of invariant V24⁺Vβ11⁺ DN T cell clones were shown to recognize CD1d expressed either by a hamster (CHO) or human B cell (C1R) line. The fine specificity of this recognition was demonstrated by the failure of these clones to recognize CD1a, b, or c transfectants. Moreover, antibody blocking studies indicated that intact CD1d, rather than peptides derived from this protein, were recognized by these clones. These results provided strong evidence that CD1d recognition by these clones was mediated directly by their TCRs.

The Vβ11 chains from these clones were sequenced to determine whether this population was monoclonal or polyclonal and whether there were structural constraints on the CDR3 region. This analysis revealed a unique Vβ11 chain with extensive N-region diversity in each of the clones isolated from a single donor, demonstrating that multiple independently derived clones contributed to this population. Sequence analysis of the V24-JQ chains also revealed a clone with distinct codon usage in the V-J junction, indicative of N-region addition. These observations suggest that the TCRs used by these clones are generated through V-(D)-J recombination mechanisms and subsequent positive selection as with conventional T cells.

The Vβ11 sequence analysis also revealed the lack of apparent structural constraints on the CDR3 region, since there was marked variability in CDR3 length, Jβ usage, and sequence. There was no suggestion of a sequence motif that distinguished the Vβ11 CDR3 regions associated with the invariant V24 chain from those associated with other noninvariant V24 chains. This pattern of CDR3 independent recognition by one or several Vβ chains could be consistent with selection or expansion by a superantigen (possibly CD1d associated). However, conventional superantigen recognition is not dependent upon a V chain CDR3. It also appeared unlikely that these heterogeneous Vβ11 chains mediated recognition of distinct CD1d-presented antigens since each clone recognized CD1d expressed by both hamster and human cells without the deliberate addition of an antigen. Therefore, the current data suggest that Vβ11 may be structurally favored as an invariant V24 partner and/or mediate direct contacts with CD1d. However, pairing of the invariant V24 with Vβ11 was not an absolute requirement for CD1d recognition since analysis of an invariant V24⁺Vβ11^– DN T cell line demonstrated that the invariant V24 can pair with other Vβs to generate CD1d-reactive TCRs.

Although CD1d recognition by multiple clones was demonstrated without the deliberate addition of an antigen, this did not rule out CD1d presentation of one or a small number of conserved ubiquitous endogenous or serum- derived antigens. CD1 has been shown to present lipid antigens (6–8, 53) and hydrophobic peptide antigens (9). Consistent with these observations, the crystal structure of murine CD1d reveals a potential deep hydrophobic antigen-binding cavity (55). The pathway(s) through which CD1 may acquire such hydrophobic or other antigens are not clear, but appear distinct from the MHC class I pathway (6, 56–58). Significantly, the cytoplasmic tails of human CD1b, c, and d, and murine CD1d contain a short tyrosine-based signal that has been implicated in trafficking from the plasma membrane to endosomal compartments (54), and a recent immunogold electron microscopy study demonstrated that a large fraction of CD1b molecules were located intracellularly in an endosomal compartment (36). Based upon these observations, one hypothesis has been that CD1 proteins are targeted to an acidic endosomal compartment and are there loaded with antigen.

To address this hypothesis in the case of CD1d, the cytoplasmic tail of CD1d was replaced with the cytoplasmic tail of CD1a, which lacks recognizable targeting motifs. CD1a proteins appear to traffic to the cell surface through the default secretory pathway and do not enter an endosomal compartment (Sugita, M., M. Brenner, and S. Porcelli, unpublished data). The chimeric protein was recognized by invariant V24⁺ DN T cell clones despite the loss of the endosomal targeting signal, indicating that endosomal trafficking mediated by this signal was not necessary for CD1d recognition by this cell population. Taken together, the data in this report indicate that T cell recognition of CD1d mediated by the invariant V24 TCR may not involve a specific antigen, although presentation of a conserved cellular antigen acquired through a pathway that is independent of the endosomal targeting motif cannot be excluded. Moreover, it remains possible that CD1d presents specific foreign antigens in vivo and that the in vitro responses reflect relatively low affinity interactions mediated by CD1d binding to diverse nonspecific antigens.

In addition to specific antigen recognition by the TCR, the activation of conventional T cells is dependent upon the recruitment of p56^lck to the TCR complex by the CD4 or CD8 accessory proteins. The invariant V24⁺ DN clones express p56^lck (data not shown) and it is very likely that there are other accessory proteins that couple it to the TCR in these cells. The consistent high level expression of NKR-P1A by human invariant V24⁺ DN T cell clones, the expression of NK1 (NKR-P1C) by the homologous murine cell population, and the presence of a p56^lck binding motif in the cytoplasmic tails of the murine NKR-P1 proteins make these clear candidate accessory proteins (59, 60). However, the presence of invariant V⁺ T cells in mouse strains that do not express NK1 or other NKR-P1 proteins argues against such a critical role for NKR-P1. It should also be noted that the human NKR-P1A protein does not contain the putative p56^lck binding site (33) and, in preliminary biochemical studies, we have been unable to demonstrate an association between human NKR-P1A and p56^lck (Exley, M., unpublished data).

The human invariant V24⁺ T cell clones also expressed two other C-type lectins, CD69 and CD94, encoded in a chromosomal region that has been termed the NK locus. CD94 may heterodimerize with NKG2 proteins (48), another family of C-type lectins encoded in the NK locus (47), and this complex may be an MHC class I receptor (44, 48). CD69 is an early and transient T cell activation antigen (42), but its expression by invariant V24⁺ DN T cell clones was persistent. This suggests that invariant V24⁺ DN T cells may remain in an activated state longer than conventional T cells. Alternatively, given the high level of expression of other NK locus–encoded proteins observed on invariant V24⁺ T cells, CD69 expression may reflect constitutive transcriptional activity of the NK locus in these cells which is not directly related to T cell activation.

Although the expression of NKR-P1 and CD94 at high levels suggests some relationship to NK cells, the invariant V24⁺ DN T cells did not express a number of other molecules that play roles in NK cell function, such as CD16, CD56, and CD57. In particular, the invariant V24⁺ DN T cells did not express p58 or p70 KIRs, although expression of family members not recognized by the multiple antibodies used here remains possible. Consistent with the mAb data, preliminary RT-PCR amplification experiments with consensus KIR primers have similarly failed to detect KIR expression (data not shown). This is in contrast to recent data showing that KIRs may be expressed in other T cell subpopulations (61–64). These observations indicate that the link between invariant V24⁺ DN T cells and NK cells may be transcriptional activation of the NK locus, with limited functional overlap between these cell populations.

Cytokine production by invariant V24⁺ DN T cells was also analyzed and the results supported conclusions reached in the mouse that these cells can produce significant levels of IL-4 in response to activation (20–23). However, they also produced other cytokines, particularly IFN-, at substantial levels, and their regulatory functions in vivo are probably complex. Murine NK1⁺ T cells are responsible for the acute production of IL-4 in response to anti-CD3 in vivo (23), but this type of stimulus is clearly nonphysiological. It is unlikely that the function of this cell population is to determine systemic levels of IL-4 or other cytokines, and more likely that the IL-4 produced in response to anti-CD3 stimulation reflects the primed activation state of these cells in vivo. A reasonable alternative hypothesis is that invariant V24⁺ T cells function through cell–cell interactions to provide individual CD1d⁺ target cells with IL-4, IFN-, or other cytokines that in turn direct the further proliferation and/or differentiation of these target cells.

B cells express CD1d (51) and represent one possible target cell for invariant V24⁺ T cells. However, CD1d may also be widely expressed (51, 65) and invariant V24⁺ T cells may, therefore, have functionally important interactions with a number of different cell types. In particular, the large fraction of T cells in murine bone marrow and liver that are NK1⁺ (66, 67) presumably interact locally with CD1d⁺ cells and may play roles in regulating B cell maturation, myeloid development, or hepatic immune function. Finally, recent reports indicate that loss of invariant V24⁺ T cells in humans or of the homologous NK1⁺ T cell population in mice is associated with disease progression in several autoimmune diseases (68–70). Although the precise functions of invariant V24⁺ T cells and their murine homologues remain to be clarified, the conservation of this cell population and of the CD1d ligand across species suggests an important immunological function.

	Acknowledgments

Submitted: 7 March 1997
Revised: 21 April 1997

¹Abbreviations used in this paper: CHO, Chinese hamster ovary; DN, double negative; KIR, killer cell inhibitory receptor; RT, reverse transcriptase.

	References

Top Abstract Materials and Methods Results Discussion References

 

1 Martin LH, Calabi F, Lefebvre FA, Bilsland CA & Milstein C. Structure and expression of the human thymocyte antigens CD1a, CD1b, and CD1c, Proc Natl Acad Sci USA, 1987, 84, 9189–9193.[Abstract/Free Full Text]

2 Aruffo A & Seed B. Expression of cDNA clones encoding the thymocyte antigens CD1a, b, c demonstrates a hierarchy of exclusion in fibroblasts, J Immunol, 1989, 143, 1723–1730.[Abstract]

3 Balk SP, Bleicher PA & Terhorst C. Isolation and characterization of a cDNA and gene coding for a fourth CD1 molecule, Proc Natl Acad Sci USA, 1989, 86, 252–256.[Abstract/Free Full Text]

4 Blumberg RS, Gerdes D, Chott A, Porcelli SA & Balk SP. Structure and function of the CD1 family of MHC-like cell surface proteins, Immunol Rev, 1995, 147, 5–29.[Medline]

5 Porcelli SA. The CD1 family: a third lineage of antigen-presenting molecules, Adv Immunol, 1995, 59, 1–98.[Medline]

6 Porcelli S, Morita CT & Brenner MB. CD1b restricts the response of human CD4^–8^–T lymphocytes to a microbial antigen, Nature (Lond), 1992, 360, 593–597.[Medline]

7 Beckman EM, Porcelli SA, Morita CT, Behar SM, Furlong ST & Brenner MB. Recognition of a lipid antigen by CD1-restricted β⁺T cells, Nature (Lond), 1994, 372, 691–694.[Medline]

8 Sieling PA, Chatterjee D, Porcelli SA, Prigozy TI, Mazzaccaro RJ, Soriano T, Bloom BR, Brenner MB, Kronenberg M, Brennan PJ et al.. CD1-restricted T cell recognition of microbial lipoglycan antigens, Science (Wash DC), 1995, 269, 227–230.[Abstract/Free Full Text]

9 Castano AR, Tangri S, Miller JE, Holcombe HR, Jackson MR, Huse WD, Kronenberg M & Peterson PA. Peptide binding and presentation by mouse CD1, Science (Wash DC), 1995, 269, 223–226.[Abstract/Free Full Text]

10 Coles MC & Raulet DH. Class I dependence of the development of CD4⁺ CD8^– NK1.1⁺thymocytes, J Exp Med, 1994, 180, 395–399.[Abstract/Free Full Text]

11 Ohteki T & MacDonald HR. Major histocompatibility complex class I related molecules control the development of CD4⁺8^– and CD4^–8^– subsets of natural killer 1.1⁺ T cell receptor-/β⁺cells in the liver of mice, J Exp Med, 1994, 180, 699–704.[Abstract/Free Full Text]

12 Bendelac A, Killeen N, Littman DR & Schwartz RH. A subset of CD4⁺thymocytes selected by MHC class I molecules, Science (Wash DC), 1994, 263, 1774–1778.[Abstract/Free Full Text]

13 Adachi Y, Koseki H, Zijlstra M & Taniguchi M. Positive selection of invariant V14⁺T cells by non-major histocompatibility complex–encoded class I–like molecules expressed on bone marrow–derived cells, Proc Natl Acad Sci USA, 1995, 92, 1200–1204.[Abstract/Free Full Text]

14 Bendelac A, Lantz O, Quimby ME, Yewdell JW, Bennink JR & Brutkiewicz RR. CD1 recognition by mouse NK1⁺T lymphocytes, Science (Wash DC), 1995, 268, 863–865.[Abstract/Free Full Text]

15 MacDonald HR. NK1.1⁺ T cell receptor-/β⁺cells: new clues to their origin, specificity, and function, J Exp Med, 1995, 182, 633–638.[Free Full Text]

16 Bix M & Locksley RM. Natural T cells. Cells that co-express NKRP-1 and TCR, J Immunol, 1995, 155, 1020–1022.[Medline]

17 Lantz O & Bendelac A. An invariant T cell receptor 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, 1994, 180, 1097–1106.[Abstract/Free Full Text]

18 Koseki H, Asano H, Inaba T, Miyashita N, Moriwaki K, Lindahl KF, Mizutani Y, Imai K & Taniguchi M. Dominant expression of a distinctive V14⁺T-cell antigen receptor chain in mice, Proc Natl Acad Sci USA, 1991, 88, 7518–7522.[Abstract/Free Full Text]

19 Arase H, Arase N, Ogasawara K, Good RA & Onoe K. An NK1.1⁺ CD4⁺8^–single-positive thymocyte subpopulation that expresses a highly skewed T-cell antigen receptor V β family, Proc Natl Acad Sci USA, 1992, 89, 6506–6510.[Abstract/Free Full Text]

20 Hayakawa K, Lin BT & Hardy RR. Murine thymic CD4⁺T cell subsets: a subset (Thy0) that secretes diverse cytokines and overexpresses the Vβ8 T cell receptor gene family, J Exp Med, 1992, 176, 269–274.[Abstract/Free Full Text]

21 Zlotnik A, Godfrey DI, Fischer M & Suda T. Cytokine production by mature and immature CD4^–CD8^– T cells. β–T cell receptor⁺ CD4^–CD8^–T cells produce IL-4, J Immunol, 1992, 149, 1211–1215.[Abstract]

22 Arase H, Arase N, Nakagawa K, Good RA & Onoe K. NK1.1⁺ CD4⁺ CD8^–thymocytes with specific lymphokine secretion, Eur J Immunol, 1993, 23, 307–310.[Medline]

23 Yoshimoto T & Paul WE. CD4^pos, NK1.1^posT cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3, J Exp Med, 1994, 179, 1285–1295.[Abstract/Free Full Text]

24 Yoshimoto T, Bendelac A, Watson C, Hu-Li J & Paul WE. Role of NK1.1⁺T cells in a TH2 response and in immunoglobulin E production, Science (Wash DC), 1995, 270, 1845–1847.[Abstract/Free Full Text]

25 Arase H, Arase N & Saito T. Interferon production by natural killer (NK) cells and NK1.1⁺T cells upon NKR-P1 cross-linking, J Exp Med, 1996, 183, 2391–2396.[Abstract/Free Full Text]

26 Calabi F, Jarvis JM, Martin L & Milstein C. Two classes of CD1 genes, Eur J Immunol, 1989, 19, 285–292.[Medline]

27 Bradbury A, Belt KT, Neri TM, Milstein C & Calabi F. Mouse CD1 is distinct from and co-exists with TL in the same thymus, EMBO (Eur Mol Biol Organ) J, 1988, 7, 3081–3086.[Medline]

28 Balk SP, Bleicher PA & Terhorst C. Isolation and expression of cDNA encoding the murine homologues of CD1, J Immunol, 1991, 146, 768–774.[Abstract]

29 Porcelli S, Yockey CE, Brenner MB & Balk SP. Analysis of T cell antigen receptor (TCR) expression by human peripheral blood CD4^–8^–/β T cells demonstrates preferential use of several V β genes and an invariant TCR β chain, J Exp Med, 1993, 178, 1–16.[Abstract/Free Full Text]

30 Dellabona P, Casorati G, Friedli B, Angman L, Sallusto F, Tunnacliffe A, Roosneek E & Lanzavecchia A. In vivo persistence of expanded clones specific for bacterial antigens within the human T cell receptor /β CD4^–8^–subset, J Exp Med, 1993, 177, 1763–1771.[Abstract/Free Full Text]

31 Dellabona P, Padovan E, Casorati G, Brockhaus M & Lanzavecchia A. An invariant V24-JQ/Vβ11 T cell receptor is expressed in all individuals by clonally expanded CD4^–8^–T cells, J Exp Med, 1994, 180, 1171–1176.[Abstract/Free Full Text]

32 Porcelli S, Gerdes D, Fertig A & Balk SP. Human T cells expressing an invariant V24-JQ TCR are CD4^–and heterogeneous with respect to TCRβ expression, Hum Immunol, 1996, 48, 63–67.[Medline]

33 Lanier LL, Chang C & Phillips JH. Human NKR-P1A. A disulfide-linked homodimer of the C-type lectin superfamily expressed by a subset of NK and T lymphocytes, J Immunol, 1994, 153, 2417–2428.[Abstract]

34 Raulet DH & Held W. Natural killer cell receptors: the offs and ons of NK cell recognition, Cell, 1995, 82, 697–700.[Medline]

35 Lanier LL & Phillips JH. Inhibitory MHC class I receptors on NK cells and T cells, Immunol Today, 1996, 17, 86–91.[Medline]

36 Sugita M, Jackman RM, van Donselaar E, Behar SM, Rogers RA, Peters PJ, Brenner MB & Porcelli SA. Cytoplasmic tail–dependent localization of CD1b antigen-presenting molecules to MICs, Science (Wash DC), 1996, 273, 349–352.[Abstract]

37 Robertson MJ, Cochran KJ, Cameron C, Le JM, Tantravahi R & Ritz J. Characterization of a cell line, NKL, derived from an aggressive human natural killer cell leukemia, Exp Hematol, 1996, 24, 406–415.[Medline]

38 Balk SP, Ebert EC, Blumenthal RL, McDermott FV, Wucherpfennig KW, Landau SB & Blumberg RS. Oligoclonal expansion and CD1 recognition by human intestinal intraepithelial lymphocytes, Science (Wash DC), 1991, 253, 1411–1415.[Abstract/Free Full Text]

39 Takebe Y, Seiki M, Fujisawa J, Hoy P, Yokota K, Arai K, Yoshida M & Arai N. SR promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat, Mol Cell Biol, 1988, 8, 466–472.[Abstract/Free Full Text]

40 Rhodes J, Chen H, Hall SR, Beesley JE, Jenkins DC, Collins P & Zheng B. Therapeutic potentiation of the immune system by costimulatory Schiff–base-forming drugs, Nature (Lond), 1995, 377, 71–75.[Medline]

41 Padovan E, Casorati G, Dellabona P, Meyer S, Brockhaus M & Lanzavecchia A. Expression of two T cell receptor chains: dual receptor T cells, Science (Wash DC), 1993, 262, 422–424.[Abstract/Free Full Text]

42 Hamann J, Fiebig H & Strauss M. Expression cloning of the early activation antigen CD69, a type II integral membrane protein with a C-type lectin domain, J Immunol, 1993, 150, 4920–4927.[Abstract]

43 Aramburu J, Balboa MA, Ramirez A, Silva A, Acevedo A, Sanchez-Madrid F, De Landazuri MO & Lopez-Botet M. A novel functional cell surface dimer (Kp43) expressed by natural killer cells and T cell receptor-/⁺T lymphocytes. I. Inhibition of the IL-2–dependent proliferation by anti-Kp43 monoclonal antibody, J Immunol, 1990, 144, 3238–3247.[Abstract]

44 Moretta A, Vitale M, Sivori S, Bottino C, Morelli L, Augugliaro R, Barbaresi M, Pende D, Ciccone E & Lopez-Botet M. Human natural killer cell receptors for HLA–class I molecules. Evidence that the Kp43 (CD94) molecule functions as receptor for HLA-B alleles, J Exp Med, 1994, 180, 545–555.[Abstract/Free Full Text]

45 Chang C, Rodriguez A, Carretero M, Lopez-Botet M, Phillips JH & Lanier LL. Molecular characterization of human CD94: a type II membrane glycoprotein related to the C-type lectin superfamily, Eur J Immunol, 1995, 25, 2433–2437.[Medline]

46 Phillips JH, Chang C, Mattson J, Gumperz JE, Parham P & Lanier LL. CD94 and a novel associated protein (94AP) form a NK cell receptor involved in the recognition of HLA-A, HLA-B, and HLA-C allotypes, Immunity, 1996, 5, 163–172.[Medline]

47 Houchins JP, Yabe T, McSherry C & Bach FH. DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells, J Exp Med, 1991, 173, 1017–1020.[Abstract/Free Full Text]

48 Lazetic S, Chang C, Houchins JP, Lanier LL & Phillips JH. Human natural killer cell receptors involved in MHC class I recognition are disulfide-linked heterodomers of CD94 and NKG2 subunits, J Immunol, 1996, 157, 4741–4745.[Abstract]

49 Webb LM & Feldmann M. Critical role of CD28/B7 costimulation in the development of human Th2 cytokine-producing cells, Blood, 1995, 86, 3479–3486.[Abstract/Free Full Text]

50 Brinkmann V, Kinzel B & Kristofic C. TCR-independent activation of human CD4⁺ 45RO^–T cells by anti-CD28 plus IL-2: induction of clonal expansion and priming for a Th2 phenotype, J Immunol, 1996, 156, 4100–4106.[Abstract]

51 Blumberg RS, Terhorst C, Bleicher P, McDermott FV, Allan CH, Landau SB, Trier JS & Balk SP. Expression of a nonpolymorphic MHC class I–like molecule, CD1D, by human intestinal epithelial cells, J Immunol, 1991, 147, 2518–2524.[Abstract/Free Full Text]

52 Zemmour J, Little AM, Schendel DJ & Parham P. The HLA-A,B "negative" mutant cell line C1R expresses a novel HLA-B35 allele, which also has a point mutation in the translation initiation codon, J Immunol, 1992, 148, 1941–1948.[Abstract]

53 Beckman EM, Melian A, Behar SM, Sieling PA, Chatterjee D, Furlong ST, Matsumoto R, Rosat JP, Modlin RL & Porcelli SA. CD1c restricts responses of mycobacteria-specific T cells. Evidence for antigen presentation by a second member of the human CD1 family, J Immunol, 1996, 157, 2795–2803.[Abstract]

54 Sandoval IV & Bakke O. Targeting of membrane proteins to endosomes and lysosomes, Trends Cell Biol, 1994, 4, 292–297.[Medline]

55 Zeng, Z.H., A.R. Castano, B. Segelke, E.A. Stura, P.A. Peterson, and I.A. Wilson. 1997. The crystal structure of murine CD1: an MHC-like fold but with a large hydrophobic antigen binding groove. Science (Wash. DC). In press.

56 Hanau D, Fricker D, Bieber T, Esposito-Farese ME, Bausinger H, Cazenave JP, Donato L, Tongio MM & de la Salle H. CD1 expression is not affected by human peptide transporter deficiency, Hum Immunol, 1994, 41, 61–68.[Medline]

57 Brutkiewicz RR, Bennink JR, Yewdell JW & Bendelac A. TAP-independent, β2-microglobulin–dependent surface expression of functional mouse CD1.1, J Exp Med, 1995, 182, 1913–1919.[Abstract/Free Full Text]

58 Joyce S, Negishi I, Boesteanu A, DeSilva AD, Sharma P, Chorney MJ, Loh DL & van Kaer L. Expansion of natural (NK1⁺) T cells that express β T cell receptors in TAP-1 null and thymus leukemia antigen positive mice, J Exp Med, 1996, 184, 1579–1584.[Abstract/Free Full Text]

59 Turner JM, Brodsky MH, Irving BA, Levin SD, Perlmutter RM & Littman DR. Interaction of the unique N-terminal region of tyrosine kinase p56^lckwith cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs, Cell, 1990, 60, 755–765.[Medline]

60 Giorda R & Trucco M. Mouse NKR-P1. A family of genes selectively coexpressed in adherent lymphokine-activated killer cells, J Immunol, 1991, 147, 1701–1708.[Abstract]

61 Falk CS, Steinle A & Schendel DJ. Expression of HLA-C molecules confers target cell resistance to some non– major histocompatibility complex–restricted T cells in a manner analogous to allospecific natural killer cells, J Exp Med, 1995, 182, 1005–1018.[Abstract/Free Full Text]

62 Nakajima H, Tomiyama H & Takiguchi M. Inhibition of T cell recognition by receptors for MHC class I molecules, J Immunol, 1995, 155, 4139–4142.[Abstract]

63 Phillips JH, Gumperz JE, Parham P & Lanier LL. Superantigen-dependent, cell-mediated cytotoxicity inhibited by MHC class I receptors on T lymphocytes, Science (Wash DC), 1995, 268, 403–405.[Abstract/Free Full Text]

64 Mingari MC, Vitale C, Cambiaggi A, Schiavetti F, Melioli G, Ferrini S & Poggi A. Cytolytic T lymphocytes displaying natural killer (NK)-like activity: expression of NK-related functional receptors for HLA class I molecules (p58 and CD94) and inhibitory effect on the TCR-mediated target cell lysis or lymphokine production, Int Immunol, 1995, 7, 697–703.[Abstract/Free Full Text]

65 Canchis PW, Bhan AK, Landau SB, Yang L, Balk SP & Blumberg RS. Tissue distribution of the non-polymorphic major histocompatibility complex class I–like molecule, CD1d, Immunology, 1993, 80, 561–565.[Medline]

66 Watanabe H, Miyaji C, Kawachi Y, Iiai T, Ohtsuka K, Iwanage T, Takahashi-Iwanaga H & Abo T. Relationships between intermediate TCR cells and NK1.1⁺ T cells in various immune organs. NK1.1⁺T cells are present within a population of intermediate TCR cells, J Immunol, 1995, 155, 2972–2983.[Abstract]

67 Makino Y, Kanno R, Ito T, Higashino K & Taniguchi M. Predominant expression of invariant V14⁺ TCR chain in NK1.1⁺T cell populations, Int Immunol, 1995, 7, 1157–1161.[Abstract/Free Full Text]

68 Sumida T, Sakamoto A, Murata H, Makino Y, Takahashi H, Yoshida S, Nishioka K, Iwamoto I & Taniguchi M. Selective reduction of T cells bearing invariant V24JQ antigen receptor in patients with systemic sclerosis, J Exp Med, 1995, 182, 1163–1168.[Abstract/Free Full Text]

69 Mieza MA, Itoh T, Cui J Q, Makino Y, Kawano T, Tsuchida K, Koike T, Shirai T, Yagita H, Matsuzawa A et al.. Selective reduction of V14⁺NK T cells associated with disease development in autoimmune-prone mice, J Immunol, 1996, 156, 4035–4040.[Abstract]

70 Gombert JM, Herbelin A, Tancrede-Bohin E, Dy M, Chatenoud L, Carnaud C & Bach JF. Early defect of immunoregulatory T cells in autoimmune diabetes, C R Acad Sci III, 1996, 319, 125–129.[Medline]

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• Patterson, S., Chaidos, A., Neville, D. C. A., Poggi, A., Butters, T. D., Roberts, I. A. G., Karadimitris, A. (2008). Human Invariant NKT Cells Display Alloreactivity Instructed by Invariant TCR-CD1d Interaction and Killer Ig Receptors. J. Immunol. 181: 3268-3276 [Abstract] [Full Text]  
• Peaper, D. R., Cresswell, P. (2008). The redox activity of ERp57 is not essential for its functions in MHC class I peptide loading. Proc. Natl. Acad. Sci. USA 105: 10477-10482 [Abstract] [Full Text]  
• Waziri, A., Killory, B., Ogden, A. T. III, Canoll, P., Anderson, R. C. E., Kent, S. C., Anderson, D. E., Bruce, J. N. (2008). Preferential In Situ CD4+CD56+ T Cell Activation and Expansion within Human Glioblastoma. J. Immunol. 180: 7673-7680 [Abstract] [Full Text]  
• Yamaura, A., Hotta, C., Nakazawa, M., Van Kaer, L., Minami, M. (2008). Human invariant V{alpha}24+ natural killer T cells acquire regulatory functions by interacting with IL-10-treated dendritic cells. Blood 111: 4254-4263 [Abstract] [Full Text]  
• Uemura, Y., Suzuki, M., Liu, T.-Y., Narita, Y., Hirata, S., Ohyama, H., Ishihara, O., Matsushita, S. (2008). Role of human non-invariant NKT lymphocytes in the maintenance of type 2 T helper environment during pregnancy. Int Immunol 20: 405-412 [Abstract] [Full Text]  
• Oshima, T., Sonoda, K.-H., Nakao, S., Hijioka, K., Taniguchi, M., Ishibashi, T. (2008). Protective Role for CD1d-Reactive Invariant Natural Killer T Cells in Cauterization-Induced Corneal Inflammation. IOVS 49: 105-112 [Abstract] [Full Text]  
• Vasan, S., Poles, M. A., Horowitz, A., Siladji, E. E., Markowitz, M., Tsuji, M. (2007). Function of NKT cells, potential anti-HIV effector cells, are improved by beginning HAART during acute HIV-1 infection. Int Immunol 0: dxm055v1- [Abstract] [Full Text]  
• Coppieters, K., Van Beneden, K., Jacques, P., Dewint, P., Vervloet, A., Vander Cruyssen, B., Van Calenbergh, S., Chen, G., Franck, R. W., Verbruggen, G., Deforce, D., Matthys, P., Tsuji, M., Rottiers, P., Elewaut, D. (2007). A Single Early Activation of Invariant NK T Cells Confers Long-Term Protection against Collagen-Induced Arthritis in a Ligand-Specific Manner. J. Immunol. 179: 2300-2309 [Abstract] [Full Text]  
• Hazlett, L. D., Li, Q., Liu, J., McClellan, S., Du, W., Barrett, R. P. (2007). NKT Cells Are Critical to Initiate an Inflammatory Response after Pseudomonas aeruginosa Ocular Infection in Susceptible Mice. J. Immunol. 179: 1138-1146 [Abstract] [Full Text]  
• Chen, X., Wang, X., Keaton, J. M., Reddington, F., Illarionov, P. A., Besra, G. S., Gumperz, J. E. (2007). Distinct Endosomal Trafficking Requirements for Presentation of Autoantigens and Exogenous Lipids by Human CD1d Molecules. J. Immunol. 178: 6181-6190 [Abstract] [Full Text]  
• Coppieters, K., Dewint, P., Van Beneden, K., Jacques, P., Seeuws, S., Verbruggen, G., Deforce, D., Elewaut, D. (2007). NKT cells: manipulable managers of joint inflammation. Rheumatology (Oxford) 46: 565-571 [Abstract] [Full Text]  
• Russano, A. M., Bassotti, G., Agea, E., Bistoni, O., Mazzocchi, A., Morelli, A., Porcelli, S. A., Spinozzi, F. (2007). CD1-Restricted Recognition of Exogenous and Self-Lipid Antigens by Duodenal {gamma}{delta}+ T Lymphocytes. J. Immunol. 178: 3620-3626 [Abstract] [Full Text]  
• Galli, G., Pittoni, P., Tonti, E., Malzone, C., Uematsu, Y., Tortoli, M., Maione, D., Volpini, G., Finco, O., Nuti, S., Tavarini, S., Dellabona, P., Rappuoli, R., Casorati, G., Abrignani, S. (2007). Invariant NKT cells sustain specific B cell responses and memory. Proc. Natl. Acad. Sci. USA 104: 3984-3989 [Abstract] [Full Text]  
• Forestier, C., Takaki, T., Molano, A., Im, J. S., Baine, I., Jerud, E. S., Illarionov, P., Ndonye, R., Howell, A. R., Santamaria, P., Besra, G. S., DiLorenzo, T. P., Porcelli, S. A. (2007). Improved Outcomes in NOD Mice Treated with a Novel Th2 Cytokine-Biasing NKT Cell Activator. J. Immunol. 178: 1415-1425 [Abstract] [Full Text]  
• Paduraru, C., Spiridon, L., Yuan, W., Bricard, G., Valencia, X., Porcelli, S. A., Illarionov, P. A., Besra, G. S., Petrescu, S. M., Petrescu, A.-J., Cresswell, P. (2006). An N-Linked Glycan Modulates the Interaction between the CD1d Heavy Chain and beta2-Microglobulin. J. Biol. Chem. 281: 40369-40378 [Abstract] [Full Text]  
• Raghuraman, G., Geng, Y., Wang, C.-R. (2006). IFN-beta-Mediated Up-Regulation of CD1d in Bacteria-Infected APCs. J. Immunol. 177: 7841-7848 [Abstract] [Full Text]  
• Hong, C., Lee, H., Oh, M., Kang, C.-Y., Hong, S., Park, S.-H. (2006). CD4+ T Cells in the Absence of the CD8+ Cytotoxic T Cells Are Critical and Sufficient for NKT Cell-Dependent Tumor Rejection. J. Immunol. 177: 6747-6757 [Abstract] [Full Text]  
• Im, J. S., Tapinos, N., Chae, G.-T., Illarionov, P. A., Besra, G. S., DeVries, G. H., Modlin, R. L., Sieling, P. A., Rambukkana, A., Porcelli, S. A. (2006). Expression of CD1d Molecules by Human Schwann Cells and Potential Interactions with Immunoregulatory Invariant NK T Cells. J. Immunol. 177: 5226-5235 [Abstract] [Full Text]  
• Ilyinskii, P. O., Wang, R., Balk, S. P., Exley, M. A. (2006). CD1d Mediates T-Cell-Dependent Resistance to Secondary Infection with Encephalomyocarditis Virus (EMCV) In Vitro and Immune Response to EMCV Infection In Vivo. J. Virol. 80: 7146-7158 [Abstract] [Full Text]  
• Lin, H., Nieda, M., Hutton, J. F., Rozenkov, V., Nicol, A. J. (2006). Comparative gene expression analysis of NKT cell subpopulations. J. Leukoc. Biol. 80: 164-173 [Abstract] [Full Text]  
• Kjer-Nielsen, L., Borg, N. A., Pellicci, D. G., Beddoe, T., Kostenko, L., Clements, C. S., Williamson, N. A., Smyth, M. J., Besra, G. S., Reid, H. H., Bharadwaj, M., Godfrey, D. I., Rossjohn, J., McCluskey, J. (2006). A structural basis for selection and cross-species reactivity of the semi-invariant NKT cell receptor in CD1d/glycolipid recognition. JEM 203: 661-673 [Abstract] [Full Text]  
• Brigl, M., van den Elzen, P., Chen, X., Meyers, J. H., Wu, D., Wong, C.-H., Reddington, F., Illarianov, P. A., Besra, G. S., Brenner, M. B., Gumperz, J. E. (2006). Conserved and Heterogeneous Lipid Antigen Specificities of CD1d-Restricted NKT Cell Receptors. J. Immunol. 176: 3625-3634 [Abstract] [Full Text]  
• Zimmer, M. I., Colmone, A., Felio, K., Xu, H., Ma, A., Wang, C.-R. (2006). A Cell-Type Specific CD1d Expression Program Modulates Invariant NKT Cell Development and Function. J. Immunol. 176: 1421-1430 [Abstract] [Full Text]  
• Lotter, H., Jacobs, T., Gaworski, I., Tannich, E. (2006). Sexual Dimorphism in the Control of Amebic Liver Abscess in a Mouse Model of Disease. Infect. Immun. 74: 118-124 [Abstract] [Full Text]  
• Aldemir, H., Prod'homme, V., Dumaurier, M.-J., Retiere, C., Poupon, G., Cazareth, J., Bihl, F., Braud, V. M. (2005). Cutting Edge: Lectin-Like Transcript 1 Is a Ligand for the CD161 Receptor. J. Immunol. 175: 7791-7795 [Abstract] [Full Text]  
• Vincent, M. S., Xiong, X., Grant, E. P., Peng, W., Brenner, M. B. (2005). CD1a-, b-, and c-Restricted TCRs Recognize Both Self and Foreign Antigens. J. Immunol. 175: 6344-6351 [Abstract] [Full Text]  
• Yasunami, Y., Kojo, S., Kitamura, H., Toyofuku, A., Satoh, M., Nakano, M., Nabeyama, K., Nakamura, Y., Matsuoka, N., Ikeda, S., Tanaka, M., Ono, J., Nagata, N., Ohara, O., Taniguchi, M. (2005). V{alpha}14 NK T cell-triggered IFN-{gamma} production by Gr-1+CD11b+ cells mediates early graft loss of syngeneic transplanted islets. JEM 202: 913-918 [Abstract] [Full Text]  
• Kent, S. C., Chen, Y., Clemmings, S. M., Viglietta, V., Kenyon, N. S., Ricordi, C., Hering, B., Hafler, D. A. (2005). Loss of IL-4 Secretion from Human Type 1a Diabetic Pancreatic Draining Lymph Node NKT Cells. J. Immunol. 175: 4458-4464 [Abstract] [Full Text]  
• Osada, T., Morse, M. A., Lyerly, H. K., Clay, T. M. (2005). Ex vivo expanded human CD4+ regulatory NKT cells suppress expansion of tumor antigen-specific CTLs. Int Immunol 17: 1143-1155 [Abstract] [Full Text]  
• Yue, S. C., Shaulov, A., Wang, R., Balk, S. P., Exley, M. A. (2005). CD1d ligation on human monocytes directly signals rapid NF-{kappa}B activation and production of bioactive IL-12. Proc. Natl. Acad. Sci. USA 102: 11811-11816 [Abstract] [Full Text]  
• Ronet, C., Darche, S., de Moraes, M. L., Miyake, S., Yamamura, T., Louis, J. A., Kasper, L. H., Buzoni-Gatel, D. (2005). NKT Cells Are Critical for the Initiation of an Inflammatory Bowel Response against Toxoplasma gondii. J. Immunol. 175: 899-908 [Abstract] [Full Text]  
• Geng, Y., Laslo, P., Barton, K., Wang, C.-R. (2005). Transcriptional Regulation of CD1D1 by Ets Family Transcription Factors. J. Immunol. 175: 1022-1029 [Abstract] [Full Text]  
• Smiley, S. T., Lanthier, P. A., Couper, K. N., Szaba, F. M., Boyson, J. E., Chen, W., Johnson, L. L. (2005). Exacerbated Susceptibility to Infection-Stimulated Immunopathology in CD1d-Deficient Mice. J. Immunol. 174: 7904-7911 [Abstract] [Full Text]  
• Sheu, B.-C., Chiou, S.-H., Lin, H.-H., Chow, S.-N., Huang, S.-C., Ho, H.-N., Hsu, S.-M. (2005). Up-regulation of Inhibitory Natural Killer Receptors CD94/NKG2A with Suppressed Intracellular Perforin Expression of Tumor-Infiltrating CD8+ T Lymphocytes in Human Cervical Carcinoma. Cancer Res. 65: 2921-2929 [Abstract] [Full Text]  
• Roura-Mir, C., Catalfamo, M., Cheng, T.-Y., Marqusee, E., Besra, G. S., Jaraquemada, D., Moody, D. B. (2005). CD1a and CD1c Activate Intrathyroidal T Cells during Graves' Disease and Hashimoto's Thyroiditis. J. Immunol. 174: 3773-3780 [Abstract] [Full Text]  
• Sieling, P. A., Torrelles, J. B., Stenger, S., Chung, W., Burdick, A. E., Rea, T. H., Brennan, P. J., Belisle, J. T., Porcelli, S. A., Modlin, R. L. (2005). The Human CD1-Restricted T Cell Repertoire Is Limited to Cross-Reactive Antigens: Implications for Host Responses against Immunologically Related Pathogens. J. Immunol. 174: 2637-2644 [Abstract] [Full Text]  
• Lin, Y., Roberts, T. J., Spence, P. M., Brutkiewicz, R. R. (2005). Reduction in CD1d expression on dendritic cells and macrophages by an acute virus infection. J. Leukoc. Biol. 77: 151-158 [Abstract] [Full Text]  
• Matsumura, Y., Moodycliffe, A. M., Nghiem, D. X., Ullrich, S. E., Ananthaswamy, H. N. (2004). Resistance of CD1d-/- Mice to Ultraviolet-Induced Skin Cancer Is Associated with Increased Apoptosis. Am. J. Pathol. 165: 879-887 [Abstract] [Full Text]  
• Plackett, T. P., Boehmer, E. D., Faunce, D. E., Kovacs, E. J. (2004). Aging and innate immune cells. J. Leukoc. Biol. 76: 291-299 [Abstract] [Full Text]  
• Gumperz, J. E. (2004). CD1d-restricted "NKT" cells and myeloid IL-12 production: an immunological crossroads leading to promotion or suppression of effective anti-tumor immune responses?. J. Leukoc. Biol. 76: 307-313 [Abstract] [Full Text]  
• Durante-Mangoni, E., Wang, R., Shaulov, A., He, Q., Nasser, I., Afdhal, N., Koziel, M. J., Exley, M. A. (2004). Hepatic CD1d Expression in Hepatitis C Virus Infection and Recognition by Resident Proinflammatory CD1d-Reactive T Cells. J. Immunol. 173: 2159-2166 [Abstract] [Full Text]  
• de Lalla, C., Galli, G., Aldrighetti, L., Romeo, R., Mariani, M., Monno, A., Nuti, S., Colombo, M., Callea, F., Porcelli, S. A., Panina-Bordignon, P., Abrignani, S., Casorati, G., Dellabona, P. (2004). Production of Profibrotic Cytokines by Invariant NKT Cells Characterizes Cirrhosis Progression in Chronic Viral Hepatitis. J. Immunol. 173: 1417-1425 [Abstract] [Full Text]  
• Campos-Martin, Y., Gomez del Moral, M., Gozalbo-Lopez, B., Suela, J., Martinez-Naves, E. (2004). Expression of Human CD1d Molecules Protects Target Cells from NK Cell-Mediated Cytolysis. J. Immunol. 172: 7297-7305 [Abstract] [Full Text]  
• Das, H., Sugita, M., Brenner, M. B. (2004). Mechanisms of V{delta}1 {gamma}{delta} T Cell Activation by Microbial Components. J. Immunol. 172: 6578-6586 [Abstract] [Full Text]  
• Sandberg, J. K., Stoddart, C. A., Brilot, F., Jordan, K. A., Nixon, D. F. (2004). Development of innate CD4+ {alpha}-chain variable gene segment 24 (V{alpha}24) natural killer T cells in the early human fetal thymus is regulated by IL-7. Proc. Natl. Acad. Sci. USA 101: 7058-7063 [Abstract] [Full Text]  
• Rauch, J., Gumperz, J., Robinson, C., Skold, M., Roy, C., Young, D. C., Lafleur, M., Moody, D. B., Brenner, M. B., Costello, C. E., Behar, S. M. (2003). Structural Features of the Acyl Chain Determine Self-phospholipid Antigen Recognition by a CD1d-restricted Invariant NKT (iNKT) Cell. J. Biol. Chem. 278: 47508-47515 [Abstract] [Full Text]  
• Tsujimura, K., Obata, Y., Kondo, E., Nishida, K., Matsudaira, Y., Akatsuka, Y., Kuzushima, K., Takahashi, T. (2003). Thymus leukemia antigen (TL)-specific cytotoxic T lymphocytes recognize the {alpha}1/{alpha}2 domain of TL free from antigenic peptides. Int Immunol 15: 1319-1326 [Abstract] [Full Text]  
• Xu, H., Chun, T., Colmone, A., Nguyen, H., Wang, C.-R. (2003). 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. 171: 4105-4112 [Abstract] [Full Text]  
• Gansuvd, B., Hubbard, W. J., Hutchings, A., Thomas, F. T., Goodwin, J., Wilson, S. B., Exley, M. A., Thomas, J. M. (2003). Phenotypic and Functional Characterization of Long-Term Cultured Rhesus Macaque Spleen-Derived NKT Cells. J. Immunol. 171: 2904-2911 [Abstract] [Full Text]  
• Thomas, S. Y., Hou, R., Boyson, J. E., Means, T. K., Hess, C., Olson, D. P., Strominger, J. L., Brenner, M. B., Gumperz, J. E., Wilson, S. B., Luster, A. D. (2003). CD1d-Restricted NKT Cells Express a Chemokine Receptor Profile Indicative of Th1-Type Inflammatory Homing Cells. J. Immunol. 171: 2571-2580 [Abstract] [Full Text]  
• Kenna, T., Mason, L. G., Porcelli, S. A., Koezuka, Y., Hegarty, J. E., O'Farrelly, C., Doherty, D. G. (2003). NKT Cells from Normal and Tumor-Bearing Human Livers Are Phenotypically and Functionally Distinct from Murine NKT Cells. J. Immunol. 171: 1775-1779 [Abstract] [Full Text]  
• Nakamura, T., Sonoda, K.-H., Faunce, D. E., Gumperz, J., Yamamura, T., Miyake, S., Stein-Streilein, J. (2003). CD4+ NKT Cells, But Not Conventional CD4+ T Cells, Are Required to Generate Efferent CD8+ T Regulatory Cells Following Antigen Inoculation in an Immune-Privileged Site. J. Immunol. 171: 1266-1271 [Abstract] [Full Text]  
• Matsuki, N., Stanic, A. K., Embers, M. E., Van Kaer, L., Morel, L., Joyce, S. (2003). Genetic Dissection of V{alpha}14J{alpha}18 Natural T Cell Number and Function in Autoimmune-Prone Mice. J. Immunol. 170: 5429-5437 [Abstract] [Full Text]  
• Gansert, J. L., Kiebler, V., Engele, M., Wittke, F., Rollinghoff, M., Krensky, A. M., Porcelli, S. A., Modlin, R. L., Stenger, S. (2003). Human NKT Cells Express Granulysin and Exhibit Antimycobacterial Activity. J. Immunol. 170: 3154-3161 [Abstract] [Full Text]  
• Capone, M., Cantarella, D., Schumann, J., Naidenko, O. V., Garavaglia, C., Beermann, F., Kronenberg, M., Dellabona, P., MacDonald, H. R., Casorati, G. (2003). Human Invariant V{alpha}24-J{alpha}Q TCR Supports the Development of CD1d-Dependent NK1.1+ and NK1.1- T Cells in Transgenic Mice. J. Immunol. 170: 2390-2398 [Abstract] [Full Text]  
• Stanic, A. K., De Silva, A. D., Park, J.-J., Sriram, V., Ichikawa, S., Hirabyashi, Y., Hayakawa, K., Van Kaer, L., Brutkiewicz, R. R., Joyce, S. (2003). Defective presentation of the CD1d1-restricted natural Va14Ja18 NKT lymphocyte antigen caused by beta -D-glucosylceramide synthase deficiency. Proc. Natl. Acad. Sci. USA 100: 1849-1854 [Abstract] [Full Text]  
• Giaccone, G., Punt, C. J. A., Ando, Y., Ruijter, R., Nishi, N., Peters, M., von Blomberg, B. M. E., Scheper, R. J., van der Vliet, H. J. J., van den Eertwegh, A. J. M., Roelvink, M., Beijnen, J., Zwierzina, H., Pinedo, H. M. (2002). A Phase I Study of the Natural Killer T-Cell Ligand {alpha}-Galactosylceramide (KRN7000) in Patients with Solid Tumors. Clin. Cancer Res. 8: 3702-3709 [Abstract] [Full Text]  
• Kang, S.-J., Cresswell, P. (2002). Calnexin, Calreticulin, and ERp57 Cooperate in Disulfide Bond Formation in Human CD1d Heavy Chain. J. Biol. Chem. 277: 44838-44844 [Abstract] [Full Text]  
• Gurney, K. B., Yang, O. O., Wilson, S. B., Uittenbogaart, C. H. (2002). TCR{gamma}{delta}+ and CD161+ Thymocytes Express HIV-1 in the SCID-hu Mouse, Potentially Contributing to Immune Dysfunction in HIV Infection. J. Immunol. 169: 5338-5346 [Abstract] [Full Text]  
• Boyson, J. E., Rybalov, B., Koopman, L. A., Exley, M., Balk, S. P., Racke, F. K., Schatz, F., Masch, R., Wilson, S. B., Strominger, J. L. (2002). CD1d and invariant NKT cells at the human maternal-fetal interface. Proc. Natl. Acad. Sci. USA 99: 13741-13746 [Abstract] [Full Text]  
• Oikawa, Y., Shimada, A., Yamada, S., Motohashi, Y., Nakagawa, Y., Irie, J.-i., Maruyama, T., Saruta, T. (2002). High Frequency of V{alpha}24+ V{beta}11+ T-Cells Observed in Type 1 Diabetes. Diabetes Care 25: 1818-1823 [Abstract] [Full Text]  
• Sfondrini, L., Besusso, D., Zoia, M. T., Rodolfo, M., Invernizzi, A. M., Taniguchi, M., Nakayama, T., Colombo, M. P., Menard, S., Balsari, A. (2002). Absence of the CD1 Molecule Up-Regulates Antitumor Activity Induced by CpG Oligodeoxynucleotides in Mice. J. Immunol. 169: 151-158 [Abstract] [Full Text]  
• Sandberg, J. K., Fast, N. M., Palacios, E. H., Fennelly, G., Dobroszycki, J., Palumbo, P., Wiznia, A., Grant, R. M., Bhardwaj, N., Rosenberg, M. G., Nixon, D. F. (2002). Selective Loss of Innate CD4+ V{alpha}24 Natural Killer T Cells in Human Immunodeficiency Virus Infection. J. Virol. 76: 7528-7534 [Abstract] [Full Text]  
• Sriram, V., Cho, S., Li, P., O'Donnell, P. W., Dunn, C., Hayakawa, K., Blum, J. S., Brutkiewicz, R. R. (2002). Inhibition of glycolipid shedding rescues recognition of a CD1+ T cell lymphoma by natural killer T (NKT) cells. Proc. Natl. Acad. Sci. USA 99: 8197-8202 [Abstract] [Full Text]  
• Roberts, T. J., Sriram, V., Spence, P. M., Gui, M., Hayakawa, K., Bacik, I., Bennink, J. R., Yewdell, J. W., Brutkiewicz, R. R. (2002). Recycling CD1d1 Molecules Present Endogenous Antigens Processed in an Endocytic Compartment to NKT Cells. J. Immunol. 168: 5409-5414 [Abstract] [Full Text]  
• Takahashi, T., Chiba, S., Nieda, M., Azuma, T., Ishihara, S., Shibata, Y., Juji, T., Hirai, H. (2002). Cutting Edge: Analysis of Human V{alpha}24+CD8+ NK T Cells Activated by {alpha}-Galactosylceramide-Pulsed Monocyte-Derived Dendritic Cells. J. Immunol. 168: 3140-3144 [Abstract] [Full Text]  
• Gumperz, J. E., Miyake, S., Yamamura, T., Brenner, M. B. (2002). Functionally Distinct Subsets of CD1d-restricted Natural Killer T Cells Revealed by CD1d Tetramer Staining. JEM 195: 625-636 [Abstract] [Full Text]  
• Exley, M. A., He, Q., Cheng, O., Wang, R.-J., Cheney, C. P., Balk, S. P., Koziel, M. J. (2002). Cutting Edge: Compartmentalization of Th1-Like Noninvariant CD1d-Reactive T Cells in Hepatitis C Virus-Infected Liver. J. Immunol. 168: 1519-1523 [Abstract] [Full Text]  
• Sonoda, K.-H., Taniguchi, M., Stein-Streilein, J. (2002). Long-Term Survival of Corneal Allografts Is Dependent on Intact CD1d-Reactive NKT Cells. J. Immunol. 168: 2028-2034 [Abstract] [Full Text]  
• van der Vliet, H. J. J., von Blomberg, B. M. E., Hazenberg, M. D., Nishi, N., Otto, S. A., van Benthem, B. H., Prins, M., Claessen, F. A., van den Eertwegh, A. J. M., Giaccone, G., Miedema, F., Scheper, R. J., Pinedo, H. M. (2002). Selective Decrease in Circulating V{alpha}24+V{beta}11+ NKT Cells During HIV Type 1 Infection. J. Immunol. 168: 1490-1495 [Abstract] [Full Text]  
• Mempel, M., Ronet, C., Suarez, F., Gilleron, M., Puzo, G., Van Kaer, L., Lehuen, A., Kourilsky, P., Gachelin, G. (2002). Natural Killer T Cells Restricted by the Monomorphic MHC Class 1b CD1d1 Molecules Behave Like Inflammatory Cells. J. Immunol. 168: 365-371 [Abstract] [Full Text]  
• Singh, A. K., Wilson, M. T., Hong, S., Olivares-Villagomez, D., Du, C., Stanic, A. K., Joyce, S., Sriram, S., Koezuka, Y., Van Kaer, L. (2001). Natural Killer T Cell Activation Protects Mice Against Experimental Autoimmune Encephalomyelitis. JEM 194: 1801-1811 [Abstract] [Full Text]  
• Gui, M., Li, J., Wen, L.-J., Hardy, R. R., Hayakawa, K. (2001). TCR{beta} Chain Influences But Does Not Solely Control Autoreactivity of V{alpha}14J281T Cells. J. Immunol. 167: 6239-6246 [Abstract] [Full Text]  
• Exley, M. A., Tahir, S. M. A., Cheng, O., Shaulov, A., Joyce, R., Avigan, D., Sackstein, R., Balk, S. P. (2001). Cutting Edge: A Major Fraction of Human Bone Marrow Lymphocytes Are Th2-Like CD1d-Reactive T Cells That Can Suppress Mixed Lymphocyte Responses. J. Immunol. 167: 5531-5534 [Abstract] [Full Text]  
• Muhammad Ali Tahir, S., Cheng, O., Shaulov, A., Koezuka, Y., Bubley, G. J., Wilson, S. B., Balk, S. P., Exley, M. A. (2001). Loss of IFN-{gamma} Production by Invariant NK T Cells in Advanced Cancer. J. Immunol. 167: 4046-4050 [Abstract] [Full Text]  
• Metelitsa, L. S., Naidenko, O. V., Kant, A., Wu, H.-W., Loza, M. J., Perussia, B., Kronenberg, M., Seeger, R. C. (2001). Human NKT Cells Mediate Antitumor Cytotoxicity Directly by Recognizing Target Cell CD1d with Bound Ligand or Indirectly by Producing IL-2 to Activate NK Cells. J. Immunol. 167: 3114-3122 [Abstract] [Full Text]  
• Dunne, J., Lynch, S., O'Farrelly, C., Todryk, S., Hegarty, J. E., Feighery, C., Doherty, D. G. (2001). Selective Expansion and Partial Activation of Human NK Cells and NK Receptor-Positive T Cells by IL-2 and IL-15. J. Immunol. 167: 3129-3138 [Abstract] [Full Text]  
• Wang, B., Geng, Y.-B., Wang, C.-R. (2001). Cd1-Restricted Nk T Cells Protect Nonobese Diabetic Mice from Developing Diabetes. JEM 194: 313-320 [Abstract] [Full Text]  
• Kamada, N., Iijima, H., Kimura, K., Harada, M., Shimizu, E., Motohashi, S.-i., Kawano, T., Shinkai, H., Nakayama, T., Sakai, T., Brossay, L., Kronenberg, M., Taniguchi, M. (2001). Crucial amino acid residues of mouse CD1d for glycolipid ligand presentation to V{{alpha}}14 NKT cells. Int Immunol 13: 853-861 [Abstract] [Full Text]  
• Campbell, J. J., Qin, S., Unutmaz, D., Soler, D., Murphy, K. E., Hodge, M. R., Wu, L., Butcher, E. C. (2001). Unique Subpopulations of CD56+ NK and NK-T Peripheral Blood Lymphocytes Identified by Chemokine Receptor Expression Repertoire. J. Immunol. 166: 6477-6482 [Abstract] [Full Text]  
• Kadowaki, N., Antonenko, S., Ho, S., Rissoan, M.-C., Soumelis, V., Porcelli, S. A., Lanier, L. L., Liu, Y.-J. (2001). Distinct Cytokine Profiles of Neonatal Natural Killer T Cells after Expansion with Subsets of Dendritic Cells. JEM 193: 1221-1226 [Abstract] [Full Text]  
• Exley, M. A., Bigley, N. J., Cheng, O., Tahir, S. M. A., Smiley, S. T., Carter, Q. L., Stills, H. F., Grusby, M. J., Koezuka, Y., Taniguchi, M., Balk, S. P. (2001). CD1d-reactive T-cell activation leads to amelioration of disease caused by diabetogenic encephalomyocarditis virus. J. Leukoc. Biol. 69: 713-718 [Abstract] [Full Text]  
• Yamazaki, K., Ohsawa, Y., Yoshie, H. (2001). Elevated Proportion of Natural Killer T Cells in Periodontitis Lesions : A Common Feature of Chronic Inflammatory Diseases. Am. J. Pathol. 158: 1391-1398 [Abstract] [Full Text]  

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