Discovery of a molecular clock that controls CD8+ T cell function and exhaustion

Abstract During cancer and chronic viral infections, the persistence of antigen progressively causes CD8+ T cells to differentiate into a dysfunctional PD1+ “exhausted” state, with reduced production inflammatory cytokines relative effector that form during acute infections. Antigen costimulation signals activate kinase cascades induce distinct cell transcription programs, but how distinguish program exhausted or transcriptional states remains poorly understood. We found members protein C (PKC) family function together as “molecular clock,” sensing agonism drive programs. Continuous stimulation PKC induces many features exhaustion, including loss IFNγ TNF, upregulation inhibitory receptors TOX, altered expression proteins in AP-1 family. Mechanistically, express several different proteins, leads degradation multiple selective maintenance only one protein, PKC-η. This “PKC switch” alters downstream signaling support reprogramming terminally state. In summary, continuous through PKCs changes output from these kinases initially at level, driving targets factor thus allowing further widespread functional characterize exhaustion. Supported by Damon Runyon Cancer Research Fellowship (DRG-2358-19) an NIH training grant, T32-CA009370.