Mycophenolic acid-treated dendritic cells generate regulatory CD4 T cells that suppress CD8 T cells allocytotoxicity

Human iT(reg) cells regulate CD8 T cell cytotoxicity.Regulatory T cells (Treg) play a crucial role in controlling immunity and transplant rejection. Two main groups of Treg have been described: antigen-induced Treg (iTreg) and natural Treg (nTreg). The ways to induce and the mechanisms of action of Treg subsets remained ill defined, particularly for their effects on CD8 T cells. CD8 T cells are major agents in the rejection of allografts; the aim of this study is to investigate the effects exerted on CD8 T cells by human CD4 iTreg induced by mycophenolic acid-treated dendritic cells. iTreg suppress the proliferation of CD8 T cells by allogeneic cellcell interaction with mature dendritic cells and irrespectively of the TCR specificity of the CD8 T cells and cellcell contact of iTreg with CD8 T cells. In our model, this suppression is independent of the action of IL-10 and TGF-1. iTreg were able to modify phenotype and inhibited IFN- and TNF- secretion by CD8 T cells. Most interestingly, iTreg inhibit the synthesis of perforin and of granzymes A and B by CD8 T cells and impaired their cytotoxicity against allogeneic targets. In summary, our study showed the involvement of iTreg in the down-regulation of cytotoxic responses mediated by CD8 T cells in an allospecific context. Following studies that have shown the existence of a regulation control exerted by iTreg on CD4 T cells and dendritic cells, this work ultimately shows that this regulation can reach CD8 T-cell functions.