Paradoxical effect of reduced costimulation in T cell-mediated colitis.
B7-1 and B7-2 play different roles in the pathogenesis of autoimmunity, but this is controversial. We analyzed colitis induced by transfer of CD45RB(high)CD4(+) T cells to RAG(-/-) recipients lacking B7-1 and/or B7-2. Surprisingly, disease was greatly accelerated in RAG(-/-) recipients deficient for either B7-1 or B7-2, especially in the B7-2(-/-) recipients. This accelerated colitis induction correlated with increased T cell division in vivo and production of Th1 cytokines. Although colitis pathogenesis following T cell transfer was inhibited in the absence of CD40L expression, CD40-CD40L interactions were not required in the B7-2(-/-) RAG(-/-) recipients. In vitro priming by APCs lacking either B7-1 or B7-2 caused decreased IL-2 production, which led to decreased CTLA-4 expression, although T cells primed in this way could respond vigorously upon restimulation by producing increased IL-2 and proinflammatory cytokines. Consistent with this mechanism, we demonstrate that blocking IL-2 early after T cell transfer accelerated colitis. Our data therefore outline a mechanism whereby synergistic costimulation by B7-1 and B7-2 molecules during priming is required for optimal IL-2 production. The consequent inhibitory effect of full CTLA-4 expression, induced by IL-2, may slow colitis, even in the absence of regulatory T cells.
Kim
Gisen
G
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
Levin
Matthew
M
Schoenberger
Stephen P
SP
Sharpe
Arlene
A
Kronenberg
Mitchell
M
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D051940:B7-2 Antigen / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D060908:CTLA-4 Antigen; D003092:Colitis / Q000276:immunology* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018398:Homeodomain Proteins; D007376:Interleukin-2; C064658:RAG-1 protein; D023201:CD40 Ligand