The Loss of TET2 Promotes CD8+ T Cell Memory Differentiation

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.