CD8 + HLA-DR + CD27 + T cells define a population of naturally occurring regulatory precursors in humans

Regulatory T reg cells are essential for immune homeostasis. While CD4 T reg cells are well characterized, CD8 T reg cells remain less understood and are primarily observed in pathological or experimental contexts. Here, we identify a naturally occurring CD8 regulatory precursor T rp cell at the steady state, defined by a CD8 + HLA-DR + CD27 + phenotype and a transcriptome resembling CD4 T reg cells. Multiomics analyses reveal activation of TCF7 and costimulatory and co-inhibitory molecules in CD8 T rp cells. CD8 T rp cells suppress T cell expansion in vitro and in vivo. In a humanized xenogeneic graft-versus-host disease (GVHD) model, they dampen T cell activation, alleviate GVHD pathology, and prolong survival without impairing antileukemia activity. Mechanistically, CD8 T rp cells promote immune regulation by inducing FOXP3 expression in both CD4 T reg cells and themselves. Their expansion also correlates with immune homeostasis restoration post–allogeneic stem cell transplantation. These findings establish CD8 T rp cells as a naturally occurring regulatory precursor population that promotes transplantation tolerance.