| dc.description.abstract | Tumor-specific CD8 T cells (TST) found in patients with cancer are unable to halt cancer progression. TST are dysfunctional and cannot produce effector cytokines or kill target cells1. TST dysfunction, also known as exhaustion, has been thought to be driven by chronic T cell receptor (TCR)/antigen stimulation over days to weeks, encoded by exhaustion/dysfunction-associated epigenetic and transcriptional programs. However, we know little about (i) the interplay between CD8 T cell function and epigenetics during the initial hours after activation in both functional (acute infection) or dysfunctional contexts (tumors) or (ii) the kinetics of CD8 T cell effector or dysfunction differentiation and relationship to cell division. Here we tracked differentiation of naive tumor-specific CD8 T cells by cell division within the first hours (0-60 hours) after antigen encounter in late tumor-bearing hosts, comparing to T cells undergoing functional effector differentiation during acute infection (E). Surprisingly, despite the fact that TST underwent similar rapid activation and cell division kinetics as E, TST were nearly completely impaired in effector function, even prior to undergoing cell division. Within hours of activation, TST underwent extensive chromatin remodeling, including hallmark chromatin accessibility changes previously characterized as “exhaustion-associated” and thought to be induced by persistent antigen encounter. Strikingly, we found that CD8 T cells in infected mice differentiated into polyfunctional effectors also within hours of antigen encounter and prior to undergoing cell division, accompanied by largescale chromatin remodeling. Our findings challenge the paradigm that chronic TCR stimulation is required to drive effector function impairment in TST and refutes the prevailing notion that cell division is required to initiate epigenetic remodeling and differentiation. Importantly, we demonstrate that continued tumor/antigen exposure drives progressive epigenetic remodeling, eventually leading to “imprinting” of the dysfunctional state. Our study defines for the first time the regulation and kinetics driving the rapid divergence of T cell fate choice prior to cell division in the context of tumors versus infection. | |
