CD4+CD25-Nrp1+ T Cells Synergize with Rapamycin to Prevent Murine Cardiac Allorejection in Immunocompetent Recipients

Abstract

Besides CD4+CD25+Foxp3+ regulatory T cells (Tregs), other immunosuppressive T cells also participated in the regulation of immune tolerance. Reportedly, neuropilin-1 (Nrp1) might be one of the molecules by which regulatory cells exert their suppressive effects. Indeed, CD4+CD25-Nrp1+ T cells exhibit potent suppressive function in autoimmune inflammatory responses. Here we investigated the specific role of CD4+CD25-Nrp1+ T cells in the setting of the transplant immune response. Through MLR assays, we found that CD4+CD25-Nrp1+ T cells suppressed the proliferation of naive CD4+CD25- T cells activated by allogeneic antigen-stimulation. Adoptive transfer of CD4+CD25-Nrp1+ T cells synergized with rapamycin to induce long-term graft survival in fully MHC-mismatched murine heart transplantation, which was associated with decreased IFN-γ, IL-17 and increased IL-10, TGF-β, Foxp3 and Nrp1 expression in the grafts. Importantly, our data indicated that CD4+CD25-Nrp1+ T cell transfer augments the accumulation of Tregs in the recipient, and creates conditions that favored induction of hyporesponsiveness of the T effector cells. In conclusion, this translational study indicates the possible therapeutic potential of CD4+CD25-Nrp1+ T cells in preventing allorejection. CD4+Nrp1+ T cells might therefore be used in bulk as a population of immunosuppressive cells with more beneficial properties concerning ex vivo isolation as compared to Foxp3+ Tregs. © 2013 Yuan et al.