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Immunity. 2018 Oct 16;49(4):678-694.e5. doi: 10.1016/j.immuni.2018.08.002. Epub 2018 Oct 9.

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

Author information

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; Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8 Canada.
3
Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095 USA.
4
Translational Research Program, Benaroya Research Institute, Seattle, WA, 98101 USA.
5
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.
6
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.

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

PMID:
30314757
DOI:
10.1016/j.immuni.2018.08.002
[Indexed for MEDLINE]

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