CD8+ T Cell Priming in Established Chronic Viral Infection Preferentially Directs Differentiation of Memory-like Cells for Sustained Immunity

Abstract

CD8+ Tcell exhaustion impedes control of chronic viral infection; yet how new Tcell responses are mounted during chronic infection is unclear. Unlike Tcells primed at the onset of infection that rapidly differentiate into effectors and exhaust, we demonstrate that virus-specific CD8+ Tcells primed after establishment of chronic LCMV infection preferentially generate memory-like transcription factor TCF1+ cells that were transcriptionally and proteomically distinct, less exhausted, and more responsive to immunotherapy. Mechanistically, adaptations of antigen-presenting cells and diminished Tcell signaling intensity promoted differentiation of the memory-like subset at the expense of rapid effector cell differentiation, which was now highly dependent on IL-21-mediated CD4+ Tcell help for its functional generation. Chronic viral infection similarly redirected de novo differentiation of tumor-specific CD8+ Tcells, ultimately preventing cancer control. Thus, targeting these Tcell stimulatory pathways could enable strategies to control chronic infection, tumors, and enhance immunotherapeutic efficacy.