To find out whether chronic viral infection, conceptually similar to cancer, quantitatively or qualitatively impacts T cell priming, Snell et al. transferred naive LCMV GP33-41-specific T cells to acutely or chronically LCMV-infected mice. Interestingly, transfer to chronically infected mice resulted in a greater self-renewing, memory-like expression pattern among CD8+ T cells, with more TCF1+ and fewer “exhausted” effector cells compared to acutely infected mice, apparently due to decreased TCR and co-stimulatory signaling by APCs. T cells primed during chronic infection were more responsive to anti-PD-1 and dependent on IL-21 for stimulation of T cell help.
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.
Author Info: (1) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. (2) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Ca
Author Info: (1) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. (2) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. (3) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada; Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8 Canada. (4) Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095 USA. (5) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. (6) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. (7) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. (8) Translational Research Program, Benaroya Research Institute, Seattle, WA, 98101 USA. (9) Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8 Canada; Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, ON, M5G 0A4 Canada. (10) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada; Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8 Canada. (11) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada; Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8 Canada. Electronic address: dbrooks@uhnresearch.ca.
