Critical influence of natural regulatory CD25+ T cells on the fate of allografts in the absence of immunosuppression

Background. 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. Methods. 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(+/+) (Al[M]RAG+) or a RAG-1(-/-) (AI[M]RAG-) background. Depletion of natural CD25+ Treg cells in AI[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 11-mismatched (C57BL/6X bml2)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 X bml2)F1 antigenpresenting cells as stimulators. Results. Male allografts were spontaneously accepted by female AI(M)RAG+ mice but readily rejected by female Al (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/6X 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-gamma, IL-5, and IL-13 in mixed lymphocyte culture in a dose-dependent manner. Conclusion. Natural CD25+ Treg cells control Th1- and Th2-type allohelperT-cell responses and thereby influence the fate of allografts in nonimmunosuppressed recipients.