CD4+CD25+ Immune Regulatory Cells Are Required for Induction of Tolerance to Alloantigen via Costimulatory Blockade

doi:10.1084/jem.193.11.1311

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. Taylor^a, Randolph J. Noelle^b, and Bruce R. Blazar^a
^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

Correspondence to: Bruce R. Blazar, Department of Pediatrics, BMT Division, University of Minnesota Cancer Center, MMC 109, 420 SE Delaware St., Minneapolis, MN 55455. Tel:612-626-2734 Fax:612-624-3913 E-mail:blaza001{at}tc.umn.edu.

Immune regulatory CD4⁺CD25⁺ cells play a vital role in the inductionand maintenance of self-tolerance and are essential for T cellhomeostasis and the prevention of autoimmunity. Induction oftolerance to allogeneic donor grafts is a clinically desirablegoal in bone marrow and solid organ transplantation. To determinewhether CD4⁺CD25⁺ cells regulate T cell responses to alloantigenand are critical for tolerance induction, murine CD4⁺ T cellswere tolerized to alloantigen via ex vivo CD40 ligand (CD40L)/CD40or CD28/cytotoxic T lymphocyte–associated antigen 4/B7blockade resulting in secondary mixed leukocyte reaction hyporesponsivenessand tolerance to alloantigen in vivo. CD4⁺CD25⁺ T cells werefound to be potent regulators of alloresponses. Depletion ofCD4⁺CD25⁺ T cells from the CD4⁺ responder population completelyabrogated ex vivo tolerance induction to alloantigen as measuredby intact responses to alloantigen restimulation in vitro andin vivo. Addback of CD4⁺CD25⁺ T cells to CD4⁺CD25^- culturesrestored tolerance induction. These data are the first to indicatethat CD4⁺CD25⁺ cells are essential for the induction of toleranceto alloantigen and have important implications for tolerance-inducingstrategies targeted at T cell costimulatory pathways.

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

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