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

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.

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Acknowledgements

We thank Werner Held (University of Lausanne, Switzerland) and Zuoming Sun (City of Hope) for providing p45 Tcf1 transgenic and β-catenin transgenic mice, respectively; Ananda Goldrath (UCSD) for sharing the B16-GP33 melanoma cells; Jian Zhang (U of Iowa) for sharing TCRα–/– mice; the University of Iowa Flow Cytometry Core facility for cell sorting, the Genomics Division of Iowa Institute of Human Genetics and Admera Health for next-generation sequencing. This study was supported by grants from the NIH (AI112579, AI121080 and AI139874 to H.-H.X., GM133712 to C.Z., and GM113961, AI147064 and AI114543 to V.P.B.), and the Veteran Affairs BLR&D Merit Review Program (BX002903) to H.-H.X.

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Q.S., with assistance from X.C. and D.B.D., performed the experiments and analyzed the data; S.H. analyzed the high-throughput sequencing data under the supervision of C.Z.; V.P.B., C.Z., and H.H.X. designed and supervised the study.

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Correspondence to Chongzhi Zang or Hai-Hui Xue.

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The authors declare no competing interests.

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Shan, Q., Hu, S., Chen, X. et al. Ectopic Tcf1 expression instills a stem-like program in exhausted CD8+ T cells to enhance viral and tumor immunity. Cell Mol Immunol (2020). https://doi.org/10.1038/s41423-020-0436-5

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Keywords

  • T cell exhaustion
  • Tcf1
  • Stem cell features

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