| First Author | Andrada E | Year | 2017 |
| Journal | EBioMedicine | Volume | 19 |
| Pages | 39-48 | PubMed ID | 28438506 |
| Mgi Jnum | J:275035 | Mgi Id | MGI:6296167 |
| Doi | 10.1016/j.ebiom.2017.04.024 | Citation | Andrada E, et al. (2017) Diacylglycerol Kinase zeta Limits Cytokine-dependent Expansion of CD8(+) T Cells with Broad Antitumor Capacity. EBioMedicine 19:39-48 |
| abstractText | 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 alpha and zeta (DGKalpha/zeta) 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 DGKalpha and zeta to antigen-independent cytotoxic functions of CD8(+) T cells. Analysis of DGKzeta-deficient mice showed an increase in bystander memory-like CD8(+) T cell populations not observed in DGKalpha-deficient mice. We demonstrate that DGKzeta limits cytokine responses in an antigen-independent manner. Cytokine-specific expansion of DGKzeta-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 DGKzeta-deficient mice engrafted with the murine A20 lymphoma. Our studies reveal a isoform-specific function for DGKzeta downstream of IL-2/IL-15-mediated expansion of innate-like cytotoxic T cells, Pharmacological manipulation of DGKzeta activity is of therapeutic interest for cytokine-directed anti-tumor treatments. |
