CD318 expression defines a novel subset of human CD8⁺ regulatory T cells

CUB domain-containing protein 1 (CDCP1; CD318) is a surface glycoprotein known as a ligand for CD6, primarily studied in tumor immunology where it associates with poor prognosis. CD318 is expressed in myeloid dendritic cells and activated monocytes associated with immunoregulatory functions. Here, selective expression of CD318 on a subset of activated human CD8⁺ T cells, but not CD4⁺ T cells, is shown, defining suppressor function of this cell population. CD318⁺ CD8 T cells exhibited reduced PD-1 and KLRG-1 expression, diminished interferon-γ and tumor necrosis factor-α production, and potent suppression of autologous CD4 and CD8 T cell activation in vitro. Notably, CD8 T cells from patients with type 1 diabetes (T1D) showed reduced CD318 induction compared with controls. Mechanistically, CD318 inhibited T cell receptor signaling independently of SHP2, while its induction required interleukin-2-dependent mTOR activation. These findings identify CD318 as a marker of human CD8⁺ T cells with implications for immune regulation and autoimmunity.