Critical Influence of Natural Regulatory CD25+ T Cells on the Fate of Allografts in the Absence of Immunosuppression

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Abstract
Allografts are occasionally accepted in the absence of immunosuppression. Because naturally occurring CD4+CD25+ regulatory T cells (natural CD25+ Treg cells) have been shown to inhibit allograft rejection, we investigated their influence on the outcome of allografts in nonimmunosuppressed mouse recipients. We compared survival times of male CBA/Ca skin grafts in female CBA/Ca recipients expressing a transgenic anti-HY T-cell receptor on a RAG-1+/+ (A1[M]RAG+) or a RAG-1−/− (A1[M]RAG−) background. Depletion of natural CD25+ Treg cells in A1[M]RAG+ mice was achieved by in vivo administration of the PC61 monoclonal antibody. The influence of natural CD25+ Treg cells on the fate of major histocompatibility complex class II-mismatched (C57BL/6× bm12)F1 skin or bm12 heart transplants in C57BL/6 recipients was also assessed. Finally, we investigated the impact of natural CD25+ Treg cells on the production of T-helper (Th)1 and Th2 cytokines in mixed lymphocyte cultures between C57BL/6 CD4+ CD25− T cells as responders and bm12 or (C57BL/6× bm12)F1 antigen-presenting cells as stimulators. Male allografts were spontaneously accepted by female A1(M)RAG+ mice but readily rejected by female A1(M)RAG+ mice depleted of natural CD25+ Treg cells by pretreatment with the PC61 monoclonal antibody. Depletion of CD25+ Treg cells also enhanced eosinophil-determined rejection of (C57BL/6× bm12)F1 skin grafts or bm12 cardiac grafts in C57BL/6 recipients. Finally, natural CD25+ Treg cells inhibited the production of interleukin (IL)-2, interferon-γ, IL-5, and IL-13 in mixed lymphocyte culture in a dose-dependent manner. Natural CD25+ Treg cells control Th1- and Th2-type allohelper T-cell responses and thereby influence the fate of allografts in nonimmunosuppressed recipients.