The Loss of TET2 Promotes CD8+ T Cell Memory Differentiation

Journal of Immunology - Tập 200 Số 1 - Trang 82-91 - 2018
Shannon A. Carty1, Mercy Gohil2, Lauren B. Banks2, Renee M. Cotton3, Matthew E. Johnson4, Erietta Stelekati5,6, Andrew D. Wells7,6,3, E. John Wherry5,6, Gary A. Koretzky8,2, Martha S. Jordan6,3
1§Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
2†Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
3Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
4The Children's Hospital of Philadelphia, Philadelphia. PA 19104
5¶Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
6‖Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and
7†Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
8#Department of Medicine, Weill Cornell Medicine, New York, NY 10065

Tóm tắt

Abstract T cell differentiation requires appropriate regulation of DNA methylation. In this article, we demonstrate that the methylcytosine dioxygenase ten-eleven translocation (TET)2 regulates CD8+ T cell differentiation. In a murine model of acute viral infection, TET2 loss promotes early acquisition of a memory CD8+ T cell fate in a cell-intrinsic manner without disrupting Ag-driven cell expansion or effector function. Upon secondary recall, TET2-deficient memory CD8+ T cells demonstrate superior pathogen control. Genome-wide methylation analysis identified a number of differentially methylated regions in TET2-deficient versus wild-type CD8+ T cells. These differentially methylated regions did not occur at the loci of differentially expressed memory markers; rather, several hypermethylated regions were identified in known transcriptional regulators of CD8+ T cell memory fate. Together, these data demonstrate that TET2 is an important regulator of CD8+ T cell fate decisions.

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