CD4-mediated signals induce T cell dysfunction in vivo.
Triggering of CD4 coreceptors on both human and murine T cells can suppress TCR/CD3-induced secretion of IL-2. We show here that pretreatment of murine CD4+ T cells with the CD4-specific mAb YTS177 inhibits the CD3-mediated activation of the IL-2 promoter factors NF-AT and AP-1. Ligation of CD4 molecules on T cells leads to a transient stimulation of extracellular signal-regulated kinase (Erk) 2, but not c-Jun N-terminal kinase (JNK) activity. Pretreatment with anti-CD4 mAb impaired anti-CD3-induced Erk2 activation. Costimulation with anti-CD28 overcame the inhibitory effect of anti-CD4 Abs, by induction of JNK activation. The in vivo relevance of these studies was demonstrated by the observation that CD4+ T cells from BALB/c mice injected with nondepleting anti-CD4 mAb were inhibited in their ability to respond to OVA Ag-induced proliferation and IL-2 secretion. Interestingly, in vivo stimulation with anti-CD28 mAb restored IL-2 secretion. Furthermore, animals pretreated with anti-CD4 elicited enhanced IL-4 secretion induced by OVA and CD28. These observations suggest that CD4-specific Abs can inhibit T cell activation by interfering with signal 1 transduced through the TCR, but potentiate those delivered through the costimulatory molecule CD28. These studies have relevance to understanding the mechanism of tolerance induced by nondepleting anti-CD4 mAb used in animal models for allograft studies, autoimmune pathologies, and for immunosuppressive therapies in humans.
Institute for Human Gene Therapy, University of Pennsylvania, Philadelphia 19104, USA. chirmule@mail.med.upenn.edu
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Chirmule
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Avots
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LakshmiTamma
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Pahwa
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Serfling
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D015704:CD4 Antigens / Q000276:immunology / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D017871:Calcium-Calmodulin-Dependent Protein Kinases