Human CD8+CD45RClowFoxp3+ Tregs with high tolerogenic activity in humanized mice and defined alloantigen specificity

Tregs play a critical role in the control of immune responses and tolerance induction; however our understanding of CD8+ Tregs is limited while they are particularly promising for therapeutic application. We report here existence of highly suppressive human CD8+CD45RClowTregs expressing Foxp3 and producing IFN?, IL-10, IL-34 and TGFß to mediate their suppressive activity. We show that CD8+CD45RClowTregs are superior to canonical CD4+CD25highCD127lowTregs for suppression of allogeneic immune responses in vitro and in vivo to delay human skin rejection and GVHD in humanized mice. Robustly expanded CD8+Tregs displayed a specific gene signature and a biased TCR repertoire. CD8+Tregs were preferentially activated by pDCs presenting a dominant MHC-II derived antigen on HLA-A*02:01 to expand and suppress alloimmune responses. Our results pave the way to breakthrough tolerogenic strategies in human