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Paradoxical Effect of Reduced Costimulation in T Cell-Mediated Colitis^1,2

Gisen Kim^*, Matthew Levin^*, Stephen P. Schoenberger, Arlene Sharpe and Mitchell Kronenberg^3,*

^* Division of Developmental Immunology; Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and Department of Pathology, Harvard Medical School, Boston, MA 02115

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^highCD4⁺ 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant P01 DK46763 (to M.K.) and a Career Development Award from the Crohn’s and Colitis Foundation of America (to G.K.).

² This is manuscript 636 from the La Jolla Institute for Allergy and Immunology.

³ Address correspondence and reprint requests to Dr. Mitchell Kronenberg, Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail address: mitch{at}liai.org

⁴ Abbreviations used in this paper: EAE, experimental allergic encephalomyelitis; LN, lymph node.

This article has been cited by other articles:

				G. Kim, O. Turovskaya, M. Levin, F. R. Byrne, J. S. Whoriskey, J. G. McCabe, and M. Kronenberg Spontaneous Colitis Occurrence in Transgenic Mice with Altered B7-Mediated Costimulation J. Immunol., October 15, 2008; 181(8): 5278 - 5288. [Abstract] [Full Text] [PDF]