Providence of the CD25 KIR CD127 FOXP3 CD8 T-cell subset determines the dynamics of tumor immune surveillance.

CD8 T-regulatory (Treg) cells are emerging as crucial components of immune system. Previous studies have reported the presence of FOXP3 CD8 Treg cells, similar to CD4 Tregs, in cancer patients which produce high levels of the immunosuppressive cytokines, IL10 and TGFβ. At an early stage of tumor development, we have identified a subset of FOXP3 CD8 CD25 KIR CD127 Treg-like cells, which are IFNγ . However, this early-induced CD8 CD25 CD127 T-cell subset is certainly distinct from the IFNγ CD8 T-effector cells. These CD8 CD25 CD127 T cells express other FOXP3 CD8 Treg cell signature markers, and can selectively suppress autoreactive HLA-E T cells as well as tumor-induced CD4 Treg cells. In contrast to FOXP3 CD8 Tregs, this subset does not inhibit effector T-cell proliferation or their functions as they are HLA-E . Adoptive transfer of this early-CD8 Treg-like subset restrained tumor growth and inhibited CD4 Treg generation that impedes the immune surveillance and impairs cancer immunotherapy. At the late stage of tumor development, when CD4 Treg cells dominate the tumor-microenvironment, CD4 Tregs mediate the clonal deletion of these tumor-suppressive FOXP3 IFNγ CD8 CD25 CD127 T cells and ensure tumor immune evasion. Our findings suggest that at an early stage of the tumor, this tumor-induced IFNγ-producing FOXP3 CD8 CD25 CD127 T-cell subset can potentiate immune surveillance by targeting HLA-E-restricted CD4 Treg cells while leaving the effector T-cell population unaffected. Hence, manipulating their profile can open up a new avenue in cancer immunotherapy.