Regulatory T cells suppress the formation of potent KLRK1 and IL-7R expressing effector CD8 T cells by limiting IL-2.

Abstract

Regulatory T cells (Tregs) are indispensable for maintaining self-tolerance by suppressing conventional T cells. On the other hand, Tregs promote tumor growth by inhibiting anticancer immunity. In this study, we identified that Tregs increase the quorum of self-reactive CD8⁺ T cells required for the induction of experimental autoimmune diabetes in mice. Their major suppression mechanism is limiting available IL-2, an essential T-cell cytokine. Specifically, Tregs inhibit the formation of a previously uncharacterized subset of antigen-stimulated KLRK1⁺ IL-7R⁺ (KILR) CD8⁺ effector T cells, which are distinct from conventional effector CD8⁺ T cells. KILR CD8⁺ T cells show superior cell-killing abilities in vivo. The administration of agonistic IL-2 immunocomplexes phenocopies the absence of Tregs, i.e., it induces KILR CD8⁺ T cells, promotes autoimmunity, and enhances antitumor responses in mice. Counterparts of KILR CD8⁺ T cells were found in the human blood, revealing them as a potential target for immunotherapy.