%0 Journal Article %J J Immunol %D 2002 %T 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. %A Schneider, Helga %A Mandelbrot, Didier A %A Greenwald, Rebecca J %A Ng, Fai %A Lechler, Robert %A Sharpe, Arlene H %A Rudd, Christopher E %K Animals %K Antigens, CD %K Antigens, CD80 %K Antigens, CD86 %K Antigens, Differentiation %K CD4-Positive T-Lymphocytes %K Cells, Cultured %K Coculture Techniques %K CTLA-4 Antigen %K Enzyme Activation %K Enzyme Inhibitors %K Enzyme Reactivators %K Immunoconjugates %K JNK Mitogen-Activated Protein Kinases %K Ligands %K MAP Kinase Signaling System %K Membrane Glycoproteins %K Mice %K Mice, Knockout %K Mitogen-Activated Protein Kinases %K Up-Regulation %X 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. %B J Immunol %V 169 %P 3475-9 %8 2002 Oct 1 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/12244135?dopt=Abstract