11 results on '"Bendelac, Albert"'
Search Results
2. Distinct APCs Explain the Cytokine Bias of &agr;-Galactosylceramide Variants In Vivo.
- Author
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Bai, Li, Constantinides, Michael G., Thomas, Seddon Y., Reboulet, Rachel, Meng, Fanyong, Roentgen, Frank, Teyton, Luc, Savage, Paul B., and Bendelac, Albert
- Subjects
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GALACTOSYLCERAMIDES , *CYTOKINES , *DENDRITIC cells , *INTERLEUKIN-12 , *CELLULAR immunity , *LABORATORY mice - Abstract
&agr;-Galactosylceramide represents a new class of vaccine adjuvants and immunomodulators that stimulate NKT cells to secrete Th1 and Th2 cytokines. Synthetic variants with short or unsaturated acyl chains exhibit a striking Th2 bias in vivo but no evidence of defect in TCR signaling or stimulation of NKT cells in vitro. Using cdldlfl/fl mice, we demonstrated that distinct APC types explained the cytokine bias in vivo. Whereas NKT stimulation by &agr;-Galactosylceramide required CD1d expression by dendritic cells (DCs), presentation of the Th2 variants was promiscuous and unaffected by DC-specific ablation of CD1d. This DC-independent stimulation failed to activate the feedback loop between DC IL-12 and NK cell IFN-&ggr;, explaining the Th2 bias. Conversely, forced presentation of the Th2 variants by DC induced high IL-12. Thus, lipid structural variations that do not alter TCR recognition can activate distinct Thl or Th2 cellular networks by changing APC targeting in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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3. A Naive-Like Population of Human CD1d-Restricted T Cells Expressing Intermediate Levels of Promyelocytic Leukemia Zinc Finger.
- Author
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Constantinides, Michael G., Picard, Damien, Savage, Adam K., and Bendelac, Albert
- Subjects
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T cells , *ZINC-finger proteins , *KILLER cells , *PHENOTYPES , *LEUKEMIA , *LYMPHOCYTES - Abstract
Rare CD1d-α-galactosylceramide-specific T cells that do not express the invariant Vα24 chain of human NKT cells were recently identified after expansion in vitro with the lipid Ag, but their phenotype and frequency in vivo and lineage relationship with NKT cells could not be elucidated. By using a CD1d tetramer-based method to enrich these cells from fresh peripheral blood, we demonstrated their naive-like CD62LhighCD45RO-CD4+ phenotype and relatively high frequency of ~10-5 in several healthy individuals. Notably, these cells expressed the NKT lineage-specific transcription promyelocytic leukemia zinc finger (PLZF), indicating a developmental relationship with NKT cells and ruling out the possibility that they were conventional MHC-restricted T cells cross-reacting against CD1d-α-galactosylceramide. Although PLZF is known to direct the effector program of NKT cells, we show in this study that the naive-like cells expressed it at a significantly lower amount than NKT cells. Further, we present mouse studies demonstrating a sharp PLZF expression threshold requirement for induction of the effector phenotype. These findings directly demonstrate in vivo the existence of naive-like CD1d-restricted human T cells marked by intermediate levels of PLZF. [ABSTRACT FROM AUTHOR]
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- 2011
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4. Prevention of type 1 diabetes by invariant NKT cells is independent of peripheral CD1d expression.
- Author
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Novak J, Beaudoin L, Park S, Griseri T, Teyton L, Bendelac A, and Lehuen A
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- Animals, Antigens, CD1d, Cell Differentiation, Diabetes Mellitus, Type 1 immunology, Islets of Langerhans immunology, Mice, Mice, Knockout, T-Lymphocytes cytology, T-Lymphocytes immunology, Thymus Gland, Transgenes, Antigens, CD1 genetics, Diabetes Mellitus, Type 1 prevention & control, Killer Cells, Natural immunology
- Abstract
Invariant NKT (iNKT) cells can prevent diabetes by inhibiting the differentiation of anti-islet T cells. We recently showed that neither iNKT cell protection against diabetes nor iNKT cell inhibition of T cell differentiation in vitro requires cytokines such as IL-4, IL-10, IL-13, and TGF-beta. In contrast, cell-cell contacts were required for iNKT cell inhibition of T cell differentiation in vitro. The present study was designed to determine whether the CD1d molecule is involved in the inhibitory function of iNKT cells. Experiments were performed in vitro and in vivo, using cells lacking CD1d expression. The in vivo experiments used CD1d-deficient mice that were either reconstituted with iNKT cells or expressed a CD1d transgene exclusively in the thymus. Both mouse models had functional iNKT cells in the periphery, even though CD1d was not expressed in peripheral tissues. Surprisingly, both in vitro inhibition of T cell differentiation by iNKT cells and mouse protection against diabetes by iNKT cells were CD1d-independent. These results reveal that iNKT cells can exert critical immunoregulatory effects in the absence of CD1d recognition and that different molecular interactions are involved in iNKT cell functions.
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- 2007
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5. Sensitivity of NK1.1-negative NKT cells to transgenic BATF defines a role for activator protein-1 in the expansion and maturation of immature NKT cells in the thymus.
- Author
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Zullo AJ, Benlagha K, Bendelac A, and Taparowsky EJ
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- Animals, Antigens, CD analysis, Antigens, CD metabolism, Antigens, Differentiation, T-Lymphocyte analysis, Antigens, Differentiation, T-Lymphocyte metabolism, Basic-Leucine Zipper Transcription Factors genetics, Cytokines genetics, Gene Expression Regulation, Developmental, Humans, Hyaluronan Receptors analysis, Hyaluronan Receptors metabolism, Killer Cells, Natural chemistry, Lectins, C-Type, Liver immunology, Mice, Mice, Transgenic, Receptor-CD3 Complex, Antigen, T-Cell analysis, Receptor-CD3 Complex, Antigen, T-Cell metabolism, Spleen immunology, T-Lymphocyte Subsets chemistry, Thymus Gland immunology, Basic-Leucine Zipper Transcription Factors metabolism, Killer Cells, Natural immunology, T-Lymphocyte Subsets immunology, Thymus Gland growth & development, Transcription Factor AP-1 physiology
- Abstract
NKT cells are glycolipid-reactive lymphocytes that express markers and perform functions common to both T lymphocytes and NK cells. Although the genetic events controlling conventional T cell development are well defined, the transcription factors and genetic programs regulating NKT cell development are only beginning to be elucidated. Previously, we described the NKT cell-deficient phenotype of transgenic (Tg) mice constitutively expressing B cell-activating transcription factor (BATF), a basic leucine zipper protein and inhibitor of AP-1. In this study, we show that Tg BATF targets the majority of Valpha14Jalpha281 (Valpha14i(7)) NKT cells, regardless of CD4 expression and Vbeta gene usage. The residual NKT cells in the thymus of BATF-Tg mice are CD44(+), yet are slow to display the NK1.1 marker characteristic of mature cells. As a population, BATF-expressing NKT cells are TCRbeta/CD3epsilon(low), but express normal levels of CD69, suggesting a failure to expand appropriately following selection. Consistent with the sensitivity of NKT cells to BATF-induced changes in AP-1 activity, we detect a full complement of AP-1 basic leucine zipper proteins in wild-type NKT cells isolated from the thymus, spleen, and liver, and show that AP-1 DNA-binding activity and cytokine gene transcription are induced in NKT cells within a few hours of glycolipid Ag exposure. This study is the first to characterize AP-1 activity in NKT cells and implicates the integrity of this transcription factor complex in developmental events essential to the establishment of this unique T cell subset in the thymus.
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- 2007
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6. Cutting edge: impaired glycosphingolipid trafficking and NKT cell development in mice lacking Niemann-Pick type C1 protein.
- Author
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Sagiv Y, Hudspeth K, Mattner J, Schrantz N, Stern RK, Zhou D, Savage PB, Teyton L, and Bendelac A
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- Animals, Antigen Presentation genetics, Antigens, CD1 genetics, Antigens, CD1 metabolism, Antigens, CD1 physiology, Antigens, CD1d, Biological Transport, Active genetics, Biological Transport, Active immunology, Cells, Cultured, Glycosphingolipids antagonists & inhibitors, Glycosphingolipids immunology, Humans, Intracellular Signaling Peptides and Proteins, Killer Cells, Natural metabolism, Lymphopenia immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Niemann-Pick C1 Protein, Niemann-Pick Diseases genetics, Niemann-Pick Diseases immunology, Niemann-Pick Diseases pathology, Proteins physiology, Receptors, Antigen, T-Cell, alpha-beta biosynthesis, T-Lymphocyte Subsets metabolism, Cell Differentiation genetics, Cell Differentiation immunology, Glycosphingolipids metabolism, Killer Cells, Natural pathology, Lymphopenia genetics, Lymphopenia pathology, Proteins genetics, T-Lymphocyte Subsets pathology
- Abstract
Niemann-Pick type C1 (NPC1) is a late endosomal/lysosomal transmembrane protein involved in the cellular transport of glycosphingolipids and cholesterol that is mutated in a majority of patients with Niemann-Pick C neurodegenerative disease. We found that NPC1-deficient mice lacked Valpha14-Jalpha18 NKT cells, a major population of CD1d-restricted T cells that is conserved in humans. NPC1-deficient mice also exhibited marked defects in the presentation of Sphingomonas cell wall Ags to NKT cells and in bacterial clearance in vivo. A synthetic fluorescent alpha-glycosylceramide analog of the Sphingomonas Ag trafficked to the lysosome of wild-type cells but accumulated in the late endosome of NPC1-deficient cells. These findings reveal a blockade of lipid trafficking between endosome and lysosome as a consequence of NPC1 deficiency and suggest a common mechanism for the defects in lipid presentation and development of Valpha14-Jalpha18 NKT cells.
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- 2006
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7. Mechanisms governing B cell developmental defects in invariant chain-deficient mice.
- Author
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Benlagha K, Park SH, Guinamard R, Forestier C, Karlsson L, Chang CH, and Bendelac A
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- Animals, Antigens, CD1 genetics, Antigens, CD1d, Antigens, Differentiation, B-Lymphocyte physiology, Antigens, T-Independent physiology, B-Lymphocyte Subsets metabolism, Cell Aggregation genetics, Cell Aggregation immunology, Cell Differentiation genetics, Cell Differentiation immunology, Cell Survival genetics, Cell Survival immunology, Histocompatibility Antigens Class II physiology, Lymphocyte Count, Lymphopenia pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Spleen cytology, Spleen immunology, Spleen metabolism, Spleen pathology, Antigens, Differentiation, B-Lymphocyte genetics, B-Lymphocyte Subsets immunology, B-Lymphocyte Subsets pathology, Histocompatibility Antigens Class II genetics, Lymphopenia genetics, Lymphopenia immunology
- Abstract
Invariant chain (Ii)-deficient mice exhibit profound B cell defects that have remained poorly understood, because they could not be simply explained by impaired Ag presentation. We found that Ii deficiency induced cell autonomous defects of two distinct B cell lineages. The life span of mature follicular (FO) B cells was reduced, accounting for their markedly decreased frequency, whereas, in contrast, marginal zone (MZ) B cells accumulated. Other Ii-expressing lineages such as B1 B cells and dendritic cells were unaffected. Surprisingly, the life span of FO B cells was fully corrected in Ii/I-Abeta doubly deficient mice, revealing that Ii-free I-Abeta chains alter FO B cell survival. In contrast, the accumulation of MZ B cells was controlled by a separate mechanism independent of I-Abeta. Interestingly, in Ii-deficient mice lacking FO B cells, the MZ B cells invaded the FO zone, suggesting that intact follicules contribute to the retention of B cells in the MZ. These findings reveal unexpected consequences of Ii deficiency on the development and organization of B cell follicles.
- Published
- 2004
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8. T cell development in mice expressing CD1d directed by a classical MHC class II promoter.
- Author
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Forestier C, Park SH, Wei D, Benlagha K, Teyton L, and Bendelac A
- Subjects
- Animals, Antigen Presentation genetics, Antigens, CD1 analysis, Antigens, CD1 genetics, Antigens, CD1d, CD4-CD8 Ratio, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes pathology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes pathology, Cell Differentiation genetics, Cell Differentiation immunology, Dendritic Cells immunology, Dendritic Cells metabolism, Epithelial Cells immunology, Epithelial Cells metabolism, Histocompatibility Antigens Class II physiology, Immunohistochemistry, Killer Cells, Natural pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, T-Lymphocyte Subsets metabolism, T-Lymphocyte Subsets pathology, Thymus Gland chemistry, Thymus Gland cytology, Thymus Gland immunology, Thymus Gland pathology, Transgenes immunology, Antigens, CD1 biosynthesis, Histocompatibility Antigens Class II genetics, Promoter Regions, Genetic immunology, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets immunology
- Abstract
CD1d and nonclassical MHC molecules differ markedly from classical MHC ligands in their ability to promote the selection and differentiation of developing T cells. Whereas classical MHC-restricted T cells have a predominantly naive phenotype and a broad TCR repertoire, most other T cells have a memory and/or NKT phenotype with a restricted repertoire. Because the nonclassical ligands selecting these memory-type cells are expressed by bone marrow-derived cells, it has been suggested that the development of large repertoires of naive-type cells was dependent on the classical MHC expression pattern in the thymus cortex, high on epithelial cells and low on cortical thymocytes. We redirected CD1d expression using the classical MHC II Ealpha promoter. pEalpha-CD1d mice lacked memory-type NKT cells, but, surprisingly, they did not acquire the reciprocal ability to select a diverse population of naive CD1d-restricted cells. These findings suggest that, whereas the development of NKT cells is dependent on the pattern of CD1d expression, the absence of a broad, naive CD1d-restricted T cell repertoire may reflect intrinsic limitations of the pool of TCR genes or lipid Ags.
- Published
- 2003
- Full Text
- View/download PDF
9. The paradox of immune molecular recognition of alpha-galactosylceramide: low affinity, low specificity for CD1d, high affinity for alpha beta TCRs.
- Author
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Cantu C 3rd, Benlagha K, Savage PB, Bendelac A, and Teyton L
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- Animals, Antigens, CD1d, Binding Sites immunology, Calorimetry methods, Cell Line, Dimerization, Genes, T-Cell Receptor alpha, Genes, T-Cell Receptor beta, Isoelectric Focusing methods, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Kinetics, Lymphocyte Activation, Mice, Protein Binding immunology, Receptors, Antigen, T-Cell, alpha-beta biosynthesis, Receptors, Antigen, T-Cell, alpha-beta chemistry, Receptors, Antigen, T-Cell, alpha-beta genetics, Recombinant Proteins biosynthesis, Recombinant Proteins chemistry, Recombinant Proteins metabolism, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Thermodynamics, Transfection, Antigen Presentation immunology, Antigens, CD1 immunology, Antigens, CD1 metabolism, Epitopes, T-Lymphocyte immunology, Epitopes, T-Lymphocyte metabolism, Galactosylceramides immunology, Galactosylceramides metabolism, Receptors, Antigen, T-Cell, alpha-beta metabolism
- Abstract
CD1 resembles both class I and class II MHC but differs by the important aspect of presenting lipid/glycolipids, instead of peptides, to T cells. Biophysical studies of lipid/CD1 interactions have been limited, and kinetics of binding are in contradiction with functional studies. We have revisited this issue by designing new assays to examine the loading of CD1 with lipids. As expected for hydrophobic interactions, binding affinity was not high and had limited specificity. Lipid critical micelle concentration set the limitation to these studies. Once loaded onto CD1d, the recognition of glycolipids by alphabeta T cell receptor was studied by surface plasmon resonance using soluble Valpha14-Vbeta8.2 T cell receptors. The Valpha14 Jalpha18 chain could be paired with NK1.1 cell-derived Vbeta chain, or any Vbeta8 chain, to achieve high affinity recognition of alpha-galactosylceramide. Biophysical analysis indicated little effect of temperature or ionic strength on the binding interaction, in contrast to what has been seen in peptide/MHC-TCR studies. This suggests that there is less accommodation made by this TCR in recognizing alpha-galactosylceramide, and it can be assumed that the most rigid part of the Ag, the sugar moiety, is critical in the interaction.
- Published
- 2003
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10. The contribution of NKT cells, NK cells, and other gamma-chain-dependent non-T non-B cells to IL-12-mediated rejection of tumors.
- Author
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Park SH, Kyin T, Bendelac A, and Carnaud C
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- Animals, B-Lymphocyte Subsets immunology, Drug Administration Schedule, Graft Rejection genetics, Injections, Intralesional, Injections, Intraperitoneal, Injections, Intravenous, Injections, Subcutaneous, Interleukin Receptor Common gamma Subunit, Interleukin-12 administration & dosage, Interleukin-12 therapeutic use, Lymphocyte Activation immunology, Lymphocyte Depletion, Melanoma, Experimental genetics, Melanoma, Experimental immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Tumor Cells, Cultured, Antineoplastic Agents administration & dosage, Antineoplastic Agents therapeutic use, Graft Rejection immunology, Interleukin-12 physiology, Killer Cells, Natural immunology, Melanoma, Experimental prevention & control, Receptors, Interleukin-7 physiology, T-Lymphocyte Subsets immunology
- Abstract
IL-12 is a potent cytokine that impairs the growth of several tumors in vivo in natural as well as in therapeutic conditions. Although IL-12 can enhance a number of immunological antitumor mechanisms, including those mediated by NK cells and CTL, recent reports have suggested that the mouse CD1d-restricted V alpha 14-J alpha 18 NKT cell was the essential cell type recruited in most, if not all tumor rejection models, including the B16 melanoma. In this study, we have examined and compared the role of NKT cells, T cells, NK cells, and other non-T non-B cells in the rejection of B16 melanoma cells after exogenous administration of IL-12. Surprisingly, our results failed to confirm a necessary role for NKT cells in this model. Instead, we found that NK cells mediated the rejection of liver metastases, whereas other gamma c-dependent non-T non-B cells, possibly lymphoid dendritic cells, were required for rejection of skin tumors. These findings challenge the view that NKT cells are systematically required for IL-12-mediated rejection of tumors, and instead reveal that a variety of effector pathways can be recruited depending on the tumor microenvironment.
- Published
- 2003
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11. Glycosylphosphatidylinositol-anchored mucin-like glycoproteins from Trypanosoma cruzi bind to CD1d but do not elicit dominant innate or adaptive immune responses via the CD1d/NKT cell pathway.
- Author
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Procópio DO, Almeida IC, Torrecilhas AC, Cardoso JE, Teyton L, Travassos LR, Bendelac A, and Gazzinelli RT
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- Animals, Antibodies, Protozoan biosynthesis, Antibodies, Protozoan blood, Antigens, CD1 biosynthesis, Antigens, CD1 genetics, Antigens, CD1 physiology, Antigens, CD1d, Binding, Competitive immunology, Carbohydrate Sequence, Cells, Cultured, Chagas Disease genetics, Chagas Disease immunology, Cytokines biosynthesis, Female, Genetic Predisposition to Disease, Glycoproteins physiology, Glycosylphosphatidylinositols administration & dosage, Glycosylphosphatidylinositols chemistry, Glycosylphosphatidylinositols physiology, Immunity, Innate genetics, Killer Cells, Natural metabolism, Killer Cells, Natural parasitology, Macrophage Activation genetics, Macrophage Activation immunology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Mucins administration & dosage, Mucins chemistry, Mucins physiology, Protozoan Proteins immunology, Protozoan Proteins metabolism, Signal Transduction genetics, T-Lymphocyte Subsets metabolism, T-Lymphocyte Subsets parasitology, Trypanosoma cruzi chemistry, Trypanosoma cruzi immunology, Antigens, CD1 metabolism, Glycoproteins metabolism, Glycosylphosphatidylinositols metabolism, Killer Cells, Natural immunology, Mucins metabolism, Signal Transduction immunology, T-Lymphocyte Subsets immunology, Trypanosoma cruzi metabolism
- Abstract
It has been proposed that self and protozoan-derived GPI anchors are natural ligands of CD1d. In this study, we investigated the ability of GPI anchors from Trypanosoma cruzi to bind to CD1d and mediate activation of NKT cells. We observed that GPI-anchored mucin-like glycoproteins (GPI mucins), glycoinositolphospholipids (GIPLs), and their phosphatidylinositol moieties bind to rCD1d and inhibit the stimulation of a NKT hybridoma by the alpha-galactosylceramide-CD1 complex. However, these GPI anchors and related structures were unable to activate NKT cells in vitro or in vivo. We found that high titers of Ab anti-GPI mucins, but not anti-GIPLs, were detected in sera from wild-type as well as in TAP1(-/-), CD1d(-/-), and MHC class II(-/-) mice after immunization. However, T-dependent anti-GPI mucin Ab isotypes, such as IgG1, IgG2a, IgG2b, and IgG3, were absent on MHC class II(-/-), but were conserved in CD1d(-/-) and TAP1(-/-) mice. Furthermore, we found that CD1d(-/-) mice presented a robust cytokine as well as anti-GPI mucins and anti-GIPL Ab responses, upon infection with T. cruzi parasites. These results indicate that, despite binding to CD1d, GPI mucins and related structures expressed by T. cruzi appear not to evoke dominant CD1d-restricted immune responses in vivo. In contrast, MHC class II is critical for the production of the major Ig G isotypes against GPI mucins from T. cruzi parasites.
- Published
- 2002
- Full Text
- View/download PDF
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