Diacylglycerol Kinase ζ Limits Cytokine-dependent Expansion of CD8⁺ T Cells with Broad Antitumor Capacity.

Abstract

Interleukin-2 and -15 drive expansion/differentiation of cytotoxic CD8⁺ T cells that eliminate targets via antigen-independent killing. This property is clinically relevant for the improvement of T cell-based antitumor therapies. Diacylglycerol kinase α and ζ (DGKα/ζ) metabolize the diacylglycerol generated following antigen recognition by T lymphocytes. Enhanced expression of these two lipid kinases in tumor-infiltrating CD8⁺ T cells promotes a hyporesponsive state that contributes to tumor immune escape. Inhibition of these two enzymes might thus be of interest for potentiating conventional antigen-directed tumor elimination. In this study, we sought to characterize the contribution of DGKα and ζ to antigen-independent cytotoxic functions of CD8⁺ T cells. Analysis of DGKζ-deficient mice showed an increase in bystander memory-like CD8⁺ T cell populations not observed in DGKα-deficient mice. We demonstrate that DGKζ limits cytokine responses in an antigen-independent manner. Cytokine-specific expansion of DGKζ-deficient CD8⁺ T cells promoted enhanced differentiation of innate-like cytotoxic cells in vitro, and correlated with the more potent in vivo anti-tumor responses of DGKζ-deficient mice engrafted with the murine A20 lymphoma. Our studies reveal a isoform-specific function for DGKζ downstream of IL-2/IL-15-mediated expansion of innate-like cytotoxic T cells, Pharmacological manipulation of DGKζ activity is of therapeutic interest for cytokine-directed anti-tumor treatments.