Synergistic costimulation by both B7 molecules regulates colitis pathogenesis.
It has been reported that B7-1 and B7-2 play different roles in the pathogenesis of autoimmunity, but this issue is controversial. Here we analyzed colitis induced by transfer of CD45RB(high) CD4+ T cells to immune-deficient recipients that lack expression of either B7-1 or B7-2. Surprisingly, disease was greatly accelerated in Rag(-/-) recipients deficient for either B7 molecule. Antigen presenting cells (APCs) lacking B7-1 or B7-2 stimulated T cell proliferation in vitro, but caused suboptimal IL-2 production, leading to decreased induction of CTLA-4. The data suggest that regulatory T cells function relatively normally in B7 single-deficient recipients, but they cannot restrain the increased pathogenesis by naïve cells primed in B7 single-deficient mice. Therefore, the inhibitory effect of CTLA-4 on pathogenic T cells likely slows colitis, even in the absence of regulatory T cells. While a full block of costimulation may prevent autoimmunity, our data indicate, surprisingly, that a partial block may in some cases augment disease.
Kim
Gisen
G
La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA. mitch@liai.org
Schoenberger
Stephen P
SP
Sharpe
Arlene
A
Kronenberg
Mitchell
M
D015703:Antigens, CD / Q000276:immunology*; D000943:Antigens, Differentiation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D003093:Colitis, Ulcerative / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D007376:Interleukin-2