Abstract
FcR nonbinding anti-CD3 epsilon mAbs elicit partial TCR signaling that leads to T cell unresponsiveness and tolerance in vivo. In this study, the membrane-proximal events that promote T cell inactivation by FcR nonbinding anti-CD3 mAbs were examined. In the context of FcR nonbinding anti-CD3, TCR complexes did not aggregate and failed to translocate into glycolipid-enriched membrane microdomains. Furthermore, FcR nonbinding anti-CD3 mAbs induced tyrosine phosphorylation of the Fyn substrate Cbl, but not the ZAP-70 substrate linker for activation of T cells. Overexpression of Fyn, but not Lck, restored the mitogenicity of FcR nonbinding anti-CD3 in primary T cells. Taken together, these results suggest that Fyn mediates the partial signaling induced by TCR antagonists.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology
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CD3 Complex / immunology
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CD3 Complex / metabolism
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Cells, Cultured
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Lymphocyte Activation
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / physiology
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Membrane Microdomains / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Models, Immunological
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Phosphorylation
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-cbl
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Proto-Oncogene Proteins c-fyn
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Receptor-CD3 Complex, Antigen, T-Cell / metabolism
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Receptors, Antigen, T-Cell / antagonists & inhibitors*
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Signal Transduction*
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T-Lymphocytes / enzymology*
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T-Lymphocytes / immunology*
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Transduction, Genetic
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Ubiquitin-Protein Ligases*
Substances
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Antibodies, Monoclonal
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CD3 Complex
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Proto-Oncogene Proteins
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Receptor-CD3 Complex, Antigen, T-Cell
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Receptors, Antigen, T-Cell
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases
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Fyn protein, mouse
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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Proto-Oncogene Proteins c-fyn
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Cbl protein, mouse