The Journal of Experimental Medicine
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Published online 4 June 2001.
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© The Rockefeller University Press, 0022-1007/2001/6/1311/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 11, June 4, 2001 1311-1318

Brief Definitive Report

Cd4+Cd25+ Immune Regulatory Cells Are Required for Induction of Tolerance to Alloantigen via Costimulatory Blockade

Patricia A. Taylora, Randolph J. Noelleb, and Bruce R. Blazara

a University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, Minneapolis, Minnesota 55455
b Department of Microbiology, Dartmouth Medical College, Hanover, New Hampshire 03756
Department of Pediatrics, BMT Division, University of Minnesota Cancer Center, MMC 109, 420 SE Delaware St., Minneapolis, MN 55455.612-624-3913612-626-2734

blaza001{at}tc.umn.edu

Immune regulatory CD4+CD25+ cells play a vital role in the induction and maintenance of self-tolerance and are essential for T cell homeostasis and the prevention of autoimmunity. Induction of tolerance to allogeneic donor grafts is a clinically desirable goal in bone marrow and solid organ transplantation. To determine whether CD4+CD25+ cells regulate T cell responses to alloantigen and are critical for tolerance induction, murine CD4+ T cells were tolerized to alloantigen via ex vivo CD40 ligand (CD40L)/CD40 or CD28/cytotoxic T lymphocyte–associated antigen 4/B7 blockade resulting in secondary mixed leukocyte reaction hyporesponsiveness and tolerance to alloantigen in vivo. CD4+CD25+ T cells were found to be potent regulators of alloresponses. Depletion of CD4+CD25+ T cells from the CD4+ responder population completely abrogated ex vivo tolerance induction to alloantigen as measured by intact responses to alloantigen restimulation in vitro and in vivo. Addback of CD4+CD25+ T cells to CD4+CD25– cultures restored tolerance induction. These data are the first to indicate that CD4+CD25+ cells are essential for the induction of tolerance to alloantigen and have important implications for tolerance-inducing strategies targeted at T cell costimulatory pathways.

Key Words: regulatory T cell • IL-2 receptor {alpha} chain (CD25) • tolerance • transplantation • in vivo animal models

© 2001 The Rockefeller University Press


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