Ectopic Tcf1 expression instills a stem-like program in exhausted CD8 + T cells to enhance viral and tumor immunity

Qiang Shan; Sheng'en Hu; Xia Chen; Derek B Danahy; Vladimir P Badovinac; Chongzhi Zang; Hai-Hui Xue

doi:10.1038/s41423-020-0436-5

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Ectopic Tcf1 expression instills a stem-like program in exhausted CD8 + T cells to enhance viral and tumor immunity

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Ectopic Tcf1 expression instills a stem-like program in exhausted CD8 + T cells to enhance viral and tumor immunity

Qiang Shan, Sheng'en Hu, Xia Chen, Derek B Danahy, Vladimir P Badovinac, Chongzhi Zang and Hai-Hui Xue

Cellular & molecular immunology, Vol.18(5), pp.1262-1277

05/2021

DOI: 10.1038/s41423-020-0436-5

PMCID: PMC8093427

PMID: 32341523

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Abstract

Exhausted CD8 T (Tex) cells are dysfunctional due to persistent antigen exposure in chronic viral infection and tumor contexts. A stem cell-like Tex (Tex-stem) subset can self-renew and differentiate into terminally exhausted (Tex-term) cells. Here, we show that ectopic Tcf1 expression potently promoted the generation of Tex-stem cells in both a chronic viral infection and preclinical tumor models. Tcf1 overexpression diminished coinhibitory receptor expression and enhanced polycytokine-producing capacity while retaining a heightened responses to checkpoint blockade, leading to enhanced viral and tumor control. Mechanistically, ectopically expressed Tcf1 exploited existing and novel chromatin accessible sites as transcriptional enhancers or repressors and modulated the transcriptome by enforcing pre-existing expression patterns in Tex-stem cells, such as enhanced suppression of Blimp1 and Bim and acquisition of new downstream genes, including Mx1, Tox2, and Runx3. These findings reveal a pronounced impact of ectopic Tcf1 expression on Tex functional restoration and highlight the therapeutic potential of harnessing Tcf1-enforced transcriptional programs.

T cell exhaustion

Tcf1

Stem cell features

Details

Title: Subtitle: Ectopic Tcf1 expression instills a stem-like program in exhausted CD8 + T cells to enhance viral and tumor immunity
Creators: Qiang Shan - Hackensack Meridian School of Medicine
Sheng'en Hu - University of Virginia
Xia Chen - University of Iowa
Derek B Danahy - University of Iowa
Vladimir P Badovinac - University of Iowa
Chongzhi Zang - University of Virginia
Hai-Hui Xue - Iowa City Veterans Affairs Health Care System, Iowa City, IA, 52246, USA. haihui.xue@hmh-cdi.org
Resource Type: Journal article
Publication Details: Cellular & molecular immunology, Vol.18(5), pp.1262-1277
DOI: 10.1038/s41423-020-0436-5
PMID: 32341523
PMCID: PMC8093427
NLM abbreviation: Cell Mol Immunol
ISSN: 1672-7681
eISSN: 2042-0226
Grant note: R21 AI147064 / NIAID NIH HHS R01 AI114543 / NIAID NIH HHS R01 AI112579 / NIAID NIH HHS R01 AI121080 / NIAID NIH HHS I01 BX002903 / BLRD VA R35 GM133712 / NIGMS NIH HHS AI112579 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01 GM113961 / NIGMS NIH HHS R01 AI139874 / NIAID NIH HHS GM133712 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) GM113961 / U.S. Department of Health & Human Services | National Institutes of Health (NIH)
Language: English
Date published: 05/2021
Academic Unit: Microbiology and Immunology; Pathology
Record Identifier: 9984180923202771

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