Synergistic Costimulation by Both B7 Molecules Regulates Colitis Pathogenesis

Authors


Address for correspondence: M. Kronenberg, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA. Voice: 858-752-6540; fax: 858-225-0730.
 e-mail: mitch@liai.org

Abstract

Abstract: 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 CD45RBhigh 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.

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