[PDF][PDF] CD8+ T cell priming in established chronic viral infection preferentially directs differentiation of memory-like cells for sustained immunity

LM Snell, BL MacLeod, JC Law, I Osokine… - Immunity, 2018 - cell.com
LM Snell, BL MacLeod, JC Law, I Osokine, HJ Elsaesser, K Hezaveh, RJ Dickson, MA Gavin
Immunity, 2018cell.com
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 …
Summary
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.
cell.com