NKG2C ⁺ CD27 ^- Defines Human CD8 ⁺ Regulatory T Cells

Here we identify NKG2C ⁺ CD27 ^- as a novel surface marker unifying multiple previously reported CD8 ⁺ regulatory T cell (Treg) populations. This population displays high clonality and divides into CD226 ^- (Treg1) and CD226 ⁺ (Treg2) subsets, with Treg2 exhibiting stronger suppressive activities. Up to 35% of CD8 ⁺ T _EMRA cells are Tregs, whereas approximately 85% of CD8 ⁺ Tregs are T _EMRA cells, which increase with aging. These findings establish a unified and novel cell surface marker for CD8 ⁺ Tregs and their subsets, which resolves prior heterogeneity in the field, and show that CD8 ⁺ T _EMRA cells are a heterogeneous population that includes T cells with regulatory function. Our findings provide a critical framework for the isolation and in-depth functional characterization of CD8 ⁺ Tregs in health, aging, and disease.