CTLA-4 interacts with STAT5 and inhibits STAT5-mediated transcription.
Cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152) is a member of the immunoglobulin gene superfamily with strong homology to the receptor CD28 with which it shares the ligands CD80 and CD86. Unlike CD28, a potent costimulator of T-cell responses, CTLA-4 is transiently expressed on the cell surface of activated T cells and appears to operate predominantly as a negative regulator of T-cell proliferation. Signal transduction mechanisms utilized by CTLA-4 remain unclear although several mechanisms have been implicated. In this study, we show that the cytoplasmic domain of CTLA-4, but not of CD28, binds to STAT5 in yeast two-hybrid assay and in coimmunoprecipitation assays. Mutations of Tyr165 and Tyr182 in CTLA-4 did not abrogate the interaction of STAT5 with CTLA-4. Finally, the overexpression of CTLA-4 in Jurkat T cells inhibits STAT-mediated activation of STAT5 responsive elements. These results suggest that CTLA-4 and STAT5 interact in T cells and that this interaction is important for CTLA-4 signalling.
Laboratory for Experimental Haematology, Katholieke Universiteit Leuven, Leuven, Belgium.
M
M
Srahna
L A
LA
Van Grunsven
J E
JE
Remacle
P
P
Vandenberghe
D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D060908:CTLA-4 Antigen; D002460:Cell Line; D015723:Gene Library; D006801:Humans; D047468:Immunoprecipitation; D007376:Interleukin-2 / Q000276:immunology; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D009154:Mutation; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology; D014162:Transfection
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007376:Interleukin-2; D050799:STAT5 Transcription Factor