@article {542691, title = {Cutting edge: CTLA-4 (CD152) differentially regulates mitogen-activated protein kinases (extracellular signal-regulated kinase and c-Jun N-terminal kinase) in CD4+ T cells from receptor/ligand-deficient mice.}, journal = {J Immunol}, volume = {169}, number = {7}, year = {2002}, month = {2002 Oct 1}, pages = {3475-9}, abstract = {Although CTLA-4 (CD152) has potent inhibitory effects on T cell function, the signaling events affected by this coreceptor remain to be fully defined. Mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) act as crucial regulators of multiple aspects of cell function. Ab ligation studies have reported an inhibitory effect of CTLA-4 on TCR-induced ERK and JNK activation. In this study, we have re-examined the specificity of CTLA-4 inhibition of MAPKs by using natural ligand with ex vivo-purified CD4(+) T cells deficient in CD80 and CD86 (double knockout), or CTLA-4, CD80, and CD86 (triple knockout). Under these conditions, CTLA-4 ligation was found to up-regulate and sustain JNK activation, while inhibiting ERK activity. At the same time, JNK activation could not account for CTLA-4 induction of TGF-beta production. Our findings demonstrate that CTLA-4 cosignaling is more complex than previously appreciated, with an ability to differentially regulate members of the MAPK family in T cells.}, keywords = {Animals, Antigens, CD, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, CD4-Positive T-Lymphocytes, Cells, Cultured, Coculture Techniques, CTLA-4 Antigen, Enzyme Activation, Enzyme Inhibitors, Enzyme Reactivators, Immunoconjugates, JNK Mitogen-Activated Protein Kinases, Ligands, MAP Kinase Signaling System, Membrane Glycoproteins, Mice, Mice, Knockout, Mitogen-Activated Protein Kinases, Up-Regulation}, issn = {0022-1767}, author = {Schneider, Helga and Mandelbrot, Didier A and Greenwald, Rebecca J and Ng, Fai and Lechler, Robert and Sharpe, Arlene H and Rudd, Christopher E} }