DNA-PKcs is required for the activation and cytotoxicity of CD8+ effector T cells
| Autor: | Marie Burdine, Ana Azevedo-Pouly, Lauren Appell, Melanie Barker, Zachary Waldrip, Lyle Burdine |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 208:55.15-55.15 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Antigen-mediated activation of naïve CD8+ T cells and their differentiation into cytotoxic cells is regulated by a series of signaling mechanisms designed to maintain T cell homeostasis and proper immune responses. Given that cytotoxic CD8+ T cells are critical to the elimination of cancerous or virally infected cells as well as mediators of autoimmune diseases, GVHD and allogenic organ rejection, it is critical that we continue to dissect these mechanisms to identify promising targets for T cell modulation in the clinic. Previously, we have shown that inhibition of the kinase DNA-dependent protein kinase catalytic subunit (DNA-PKcs) reduces activity of the transcription factors NFAT, NFκB and EGR1 and production of cytokines including IL2, IL6 and IFNγ in TCR-activated T cells. Using pharmacological inhibitor and genetic approaches, we provide evidence for a novel role of DNA-PKcs in CD8+ T cell activation. Inhibition of DNA-PKcs abrogated anti-CD3/CD28 activation of CD8+ T cells as evident by reduced expression of the activation markers CD69 and CD25. Additionally, loss of DNA-PKcs activity inhibited aerobic glycolysis and proliferation of OTI-CD8+ T cells following SIINFEKL peptide stimulation. This caused reduced OTI-CD8+ T cell killing of MC38.OVA tumor cells and expression of IFNγ and the cytotoxic genes perforin and granzyme B. These results were recapitulated in DNA-PKcs-deficient CD8+ T cells isolated from an inducible Cre/DNA-PKcsfl/fl mouse model where loss of DNA-PKcs reduced expression of CD69 and CD25, IFNγ production and altered cellular metabolism. The identification of a function for DNA-PKcs in CD8+ T cell activation highlights the therapeutic potential of DNA-PKcs inhibitors on immune-related diseases. Supported by Center for Pediatric Translational Research NIH COBRE P20GM121293 |
| Databáze: | OpenAIRE |
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