BATF regulates progenitor to cytolytic effector CD8+ T cell transition during chronic viral infection. Nat Immunol 2021 Aug;22(8):996-1007
Date
07/21/2021Pubmed ID
34282329Pubmed Central ID
PMC9258987DOI
10.1038/s41590-021-00965-7Scopus ID
2-s2.0-85110654837 (requires institutional sign-in at Scopus site) 66 CitationsAbstract
During chronic viral infection, CD8+ T cells develop into three major phenotypically and functionally distinct subsets: Ly108+TCF-1+ progenitors, Ly108-CX3CR1- 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.
Author List
Chen Y, Zander RA, Wu X, Schauder DM, Kasmani MY, Shen J, Zheng S, Burns R, Taparowsky EJ, Cui WMESH terms used to index this publication - Major topics in bold
AnimalsAntigens, Ly
Basic-Leucine Zipper Transcription Factors
CD8-Positive T-Lymphocytes
CX3C Chemokine Receptor 1
Cell Differentiation
Cell Line
Female
Hepatocyte Nuclear Factor 1-alpha
Kruppel-Like Transcription Factors
Lymphocytic Choriomeningitis
Lymphocytic choriomeningitis virus
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
T-Box Domain Proteins
T-Lymphocyte Subsets