B7-independent inhibition of T cells by CTLA-4.
CTLA-4 is an inhibitory molecule that regulates T cell expansion and differentiation. CTLA-4 binding to B7-1/B7-2 is believed to be crucial for its inhibitory signal both by competing for CD28 binding to the same ligands and aggregating CTLA-4 to deliver negative signals. In this study, we demonstrate that B7 binding is not essential for CTLA-4 activity. CTLA-4 knockout T cells are hyperresponsive compared with wild-type T cells in B7-free settings. Expression of a B7-nonbinding CTLA-4 mutant inhibited T cell proliferation, cytokine production, and TCR-mediated ERK activation in otherwise CTLA-4-deficient T cells. Finally, transgenic expression of the ligand-nonbinding CTLA-4 mutant delayed the lethal lymphoproliferation observed in CTLA-4-deficient mice. These results suggest that ligand binding is not essential for the CTLA-4 function and supports an essential role for CTLA-4 signaling during T cell activation.
University of California at San Francisco Diabetes Center and Department of Medicine, University of California, San Francisco, CA 94143, USA.
Shunsuke
S
Chikuma
Abul K
AK
Abbas
Jeffrey A
JA
Bluestone
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; D008024:Ligands; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
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; D008024:Ligands; D008562:Membrane Glycoproteins