E2A-regulated epigenetic landscape promotes memory CD8 T cell differentiation. Proc Natl Acad Sci U S A 2021 Apr 20;118(16)
Date
04/17/2021Pubmed ID
33859041Pubmed Central ID
PMC8072256DOI
10.1073/pnas.2013452118Scopus ID
2-s2.0-85104381676 (requires institutional sign-in at Scopus site) 16 CitationsAbstract
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 WAuthor
Matthew Kudek MD Assistant Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBasic Helix-Loop-Helix Transcription Factors
CD8-Positive T-Lymphocytes
Cell Differentiation
Chromatin
Epigenesis, Genetic
Epigenomics
Female
Gene Expression
Gene Expression Profiling
Gene Expression Regulation
Gene Regulatory Networks
Hematopoiesis
Humans
Immunologic Memory
Lymphocyte Activation
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Sequence Analysis, RNA
Single-Cell Analysis
