Development of CD25- regulatory T cells following heart transplantation: evidence for transfer of long-term survival.

Donor-specific heart allograft acceptance can be induced in the MHC-mismatched LEW.1 W to LEW.1A rat by donor-specific transfusions. Whereas the induction phase of tolerance has been studied in detail, its maintenance remained poorly understood. Here, we performed a side-by-side comparison of CD25+ and CD25– splenic T cells of 100-day tolerant rats. Administration of CD25– T cells from tolerant rats to sublethally irradiated recipients transferred long-term graft survival. These CD25– T cells displayed a decreased donor-specific response in the mixed lymphocyte reaction and presented suppressive activity. These CD25– T cells accumulated IFN-γ, IL-10 and Foxp3 transcripts. The in vitro suppressive activity of CD25– T cells required both cell contact and soluble factors (IL-10 and IFN-γ). The CD25+ T cells from tolerant rats did not show any modification of their regulatory properties. We show that splenic CD25– T cells of tolerant rats contribute to the maintenance of tolerance following the transplantation. Our data show that regulatory T cells are not restricted to the CD4+CD25+ T cell subset and provide new insights on the mechanisms of tolerance to allograft following donor cell priming.