Mechanism and Localization of CD8 Regulatory T Cells in a Heart Transplant Model of Tolerance

Abstract

Despite accumulating evidence for the importance of allospecific CD8+ regulatory T cells (Tregs) in tolerant rodents and free immunosuppression transplant recipients, mechanisms underlying CD8+ Treg-mediated tolerance remain unclear. By using a model of transplantation tolerance mediated by CD8+ Tregs following CD40Ig treatment in rats, in this study, we show that the accumulation of tolerogenic CD8+ Tregs and plasmacytoid dendritic cells (pDCs) in allograft and spleen but not lymph nodes was associated with tolerance induction in vascularized allograft recipients. pDCs preferentially induced tolerogenic CD8+ Tregs to suppress CD4+ effector cells responses to first-donor Ags in vitro. When tolerogenic CD8+ Tregs were not in contact with CD4+ effector cells, suppression was mediated by IDO. Contact with CD4+ effector cells resulted in alternative suppressive mechanisms implicating IFN-γ and fibroleukin-2. In vivo, both IDO and IFN-γ were involved in tolerance induction, suggesting that contact with CD4+ effector cells is crucial to modulate CD8+ Tregs function in vivo. In conclusion, CD8+ Tregs and pDCs interactions were necessary for suppression of CD4+ T cells and involved different mechanisms modulated by the presence of cell contact between CD8+ Tregs, pDCs, and CD4+ effector cells.