CTLA-4 blockade of antigen-induced cell death.
While cytotoxic T lymphocyte antigen-4 (CTLA-4) negatively regulates T-cell receptor (TCR)-driven interleukin (IL)-2 production and proliferation, little is known regarding whether the coreceptor has the capacity to inhibit other events, such as Fas ligand (FasL) expression and antigen-induced cell death (AICD). In this study, it is shown that CTLA-4 expressed in a T-cell hybridoma can elicit a potent block of FasL expression and AICD. Inhibition occurred independently of CTLA-4 blockage of IL-2 production and was partially reversed by a single mutation in the cytoplasmic YVKM motif. These findings indicate that CTLA-4 can block TCR signaling prior to bifurcation of signals leading to IL-2 production and apoptosis.
da Rocha Dias
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Division of Tumor Immunology, Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Rudd
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D000069594:Abatacept; D020816:Amino Acid Motifs; D000818:Animals; D000941:Antigens / Q000276:immunology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D060908:CTLA-4 Antigen; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation; D006825:Hybridomas; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D016853:Muromonab-CD3 / Q000494:pharmacology; D017354:Point Mutation; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D018796:Immunoconjugates; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D016853:Muromonab-CD3; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D000069594:Abatacept