Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 193, Issue 11, Pages 1311-1317Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.193.11.1311
Keywords
regulatory T cell; IL-2 receptor alpha chain (CD25); tolerance; transplantation; in vivo animal models
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Funding
- NHLBI NIH HHS [R01 HL63452, 2R37 HL56067] Funding Source: Medline
- NIAID NIH HHS [R01 AI34495, P01 AI35225] Funding Source: Medline
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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.
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