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

Abstract

CD8⁺ T cell exhaustion impedes control of chronic viral infection; yet how new T cell responses are mounted during chronic infection is unclear. Unlike T cells primed at the onset of infection that rapidly differentiate into effectors and exhaust, we demonstrate that virus-specific CD8⁺ T cells 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 T cell 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⁺ T cell help for its functional generation. Chronic viral infection similarly redirected de novo differentiation of tumor-specific CD8⁺ T cells, ultimately preventing cancer control. Thus, targeting these T cell stimulatory pathways could enable strategies to control chronic infection, tumors, and enhance immunotherapeutic efficacy.

Keywords: CD4 T cell help; CD8(+) T cells; IL-21; LCMV; PDL1; T cell exhaustion; cancer; chronic infection; dendritic cells; immunotherapy; tumor immunology.