Abstract
Regulatory Treg cells are essential for immune homeostasis. While CD4 Treg cells are well characterized, CD8 Treg cells remain less understood and are primarily observed in pathological or experimental contexts. Here, we identify a naturally occurring CD8 regulatory precursor Trp cell at the steady state, defined by a CD8+HLA-DR+CD27+ phenotype and a transcriptome resembling CD4 Treg cells. Multiomics analyses reveal activation of TCF7 and costimulatory and co-inhibitory molecules in CD8 Trp cells. CD8 Trp 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 Trp cells promote immune regulation by inducing FOXP3 expression in both CD4 Treg cells and themselves. Their expansion also correlates with immune homeostasis restoration post-allogeneic stem cell transplantation. These findings establish CD8 Trp cells as a naturally occurring regulatory precursor population that promotes transplantation tolerance.