TET2 deficiency promotes CD8+ T cell memory differentiation

Abstract DNA methylation contributes to T cell differentiation. The ten-eleven translocation (TET) family of methylcytosine dioxygenases mediates active DNA demethylation. Here we demonstrate that TET2 regulates CD8+ T cell differentiation in vivo following acute viral infection. At steady-state, mice with a T-cell specific deletion of TET2 have intact thymic and peripheral T cell populations. However, following infection, TET2 loss promotes early acquisition of a memory CD8+ T cell fate in a cell-intrinsic manner without disrupting antigen-driven T cell expansion or effector function. Upon re-challenge, TET2-deficient memory CD8+ T cells exhibit superior pathogen control. Genome-wide methylation analysis of TET2-deficient versus WT CD8+ T cells identified multiple differentially methylated regions (DMRs). Analyses of DMRs suggest TET2 regulates T cell differentiation at regulatory genes, opposed to individual loci of differentially expressed memory markers. One hypermethyated region was the PRDM1 loci (encoding Blimp-1). This finding was associated with an increased Bcl6 to Blimp-1 ratio in vitro, a pattern predicted to favor memory cell fate. Taken together, our data indicate that TET2 is an important regulator of CD8+ T cell fate decisions.