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.