BATF regulates progenitor to cytolytic effector CD8+ T cell transition during chronic viral infection

Yao Chen, Ryan A. Zander, Xiaopeng Wu, David M. Schauder, Moujtaba Y. Kasmani, Jian Shen, Shikan Zheng, Robert Burns, Elizabeth J. Taparowsky, Weiguo Cui*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

During chronic viral infection, CD8+ T cells develop into three major phenotypically and functionally distinct subsets: Ly108+TCF-1+ progenitors, Ly108CX3CR1 terminally exhausted cells and the recently identified CX3CR1+ cytotoxic effector cells. Nevertheless, how CX3CR1+ effector cell differentiation is transcriptionally and epigenetically regulated remains elusive. Here, we identify distinct gene regulatory networks and epigenetic landscapes underpinning the formation of these subsets. Notably, our data demonstrate that CX3CR1+ effector cells bear a striking similarity to short-lived effector cells during acute infection. Genetic deletion of Tbx21 significantly diminished formation of the CX3CR1+ subset. Importantly, we further identify a previously unappreciated role for the transcription factor BATF in maintaining a permissive chromatin structure that allows the transition from TCF-1+ progenitors to CX3CR1+ effector cells. BATF directly bound to regulatory regions near Tbx21 and Klf2, modulating their enhancer accessibility to facilitate the transition. These mechanistic insights can potentially be harnessed to overcome T cell exhaustion during chronic infection and cancer.

Original languageEnglish (US)
Pages (from-to)996-1007
Number of pages12
JournalNature Immunology
Volume22
Issue number8
DOIs
StatePublished - Aug 2021

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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