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E2A-regulated epigenetic landscape promotes memory CD8 T cell differentiation. Proc Natl Acad Sci U S A 2021 Apr 20;118(16)

Date

04/17/2021

Pubmed ID

33859041

Pubmed Central ID

PMC8072256

DOI

10.1073/pnas.2013452118

Scopus ID

2-s2.0-85104381676   1 Citation

Abstract

During an acute viral infection, CD8 T cells encounter a myriad of antigenic and inflammatory signals of variable strength, which sets off individual T cells on their own differentiation trajectories. However, the developmental path for each of these cells will ultimately lead to one of only two potential outcomes after clearance of the infection-death or survival and development into memory CD8 T cells. How this cell fate decision is made remains incompletely understood. In this study, we explore the transcriptional changes during effector and memory CD8 T cell differentiation at the single-cell level. Using single-cell, transcriptome-derived gene regulatory network analysis, we identified two main groups of regulons that govern this differentiation process. These regulons function in concert with changes in the enhancer landscape to confer the establishment of the regulatory modules underlying the cell fate decision of CD8 T cells. Furthermore, we found that memory precursor effector cells maintain chromatin accessibility at enhancers for key memory-related genes and that these enhancers are highly enriched for E2A binding sites. Finally, we show that E2A directly regulates accessibility of enhancers of many memory-related genes and that its overexpression increases the frequency of memory precursor effector cells and accelerates memory cell formation while decreasing the frequency of short-lived effector cells. Overall, our results suggest that effector and memory CD8 T cell differentiation is largely regulated by two transcriptional circuits, with E2A serving as an important epigenetic regulator of the memory circuit.

Author List

Schauder DM, Shen J, Chen Y, Kasmani MY, Kudek MR, Burns R, Cui W

Authors

Weiguo Cui PhD Associate Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Matthew Kudek MD Assistant Professor in the Pediatrics department at Medical College of Wisconsin