Open AccessBATF regulates progenitor to cytolytic effector CD8+ T cell transition during chronic viral infection
Author(s) -
Yao Chen,
Ryan Zander,
Xiaopeng Wu,
David M. Schauder,
Moujtaba Y. Kasmani,
Jian Shen,
Shikan Zheng,
Robert T. Burns,
Elizabeth J. Taparowsky,
Weiguo Cui
Publication year - 2021
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-021-00965-7
Subject(s) - biology , effector , progenitor cell , microbiology and biotechnology , cytotoxic t cell , chromatin , cellular differentiation , cd8 , immunology , stem cell , genetics , gene , antigen , in vitro
During chronic viral infection, CD8 + T cells develop into three major phenotypically and functionally distinct subsets: Ly108 + TCF-1 + progenitors, Ly108 - CX 3 CR1 - terminally exhausted cells and the recently identified CX 3 CR1 + cytotoxic effector cells. Nevertheless, how CX 3 CR1 + 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 CX 3 CR1 + effector cells bear a striking similarity to short-lived effector cells during acute infection. Genetic deletion of Tbx21 significantly diminished formation of the CX 3 CR1 + 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 CX 3 CR1 + 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.