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.
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.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Helga
authors.initials: H
authors.lastname: Schneider
authors.forename: Didier A
authors.initials: DA
authors.lastname: Mandelbrot
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Greenwald
authors.forename: Fai
authors.initials: F
authors.lastname: Ng
authors.forename: Robert
authors.initials: R
authors.lastname: Lechler
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Rudd
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000502:physiology; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D018920:Coculture Techniques; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004793:Enzyme Reactivators / Q000494:pharmacology; D018796:Immunoconjugates; D048031:JNK Mitogen-Activated Protein Kinases; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D004791:Enzyme Inhibitors; D004793:Enzyme Reactivators; D018796:Immunoconjugates; D008024:Ligands; D008562:Membrane Glycoproteins; D000069594:Abatacept; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases