TET2 Regulates CD8⁺ T Cell Differentiation

Regulation of DNA methylation is critical for proper T cell differentiation and function. Antigen-specific CD8⁺ T cells undergo global remodeling of DNA methylation following viral infection, suggesting that DNA methylation may direct antigen-specific T cell responses. TET2 is a member of the Ten-Eleven-Translocation (TET) family, which converts 5-methylcytosine (5mC) in DNA to 5-hydroxymethylcytosine (5hmC) and subsequent intermediates ultimately leading to DNA demethylation. How TET2 regulates T cell differentiation and function is unknown. Here we demonstrate that TET2 expression is regulated by TCR signaling in primary murine T cells. Furthermore, using a novel flow cytometric assay to measure 5hmC levels on a single cell basis, we find that TCR signaling also regulates TET activity as evidenced by a rapid increase in global 5hmC levels after TCR stimulation that is blunted in TET2-deficient T cells. To determine the role of TET2 in T cell responses, we generated mice deficient in TET2 in the T cell compartment (TET2^fl/flCD4Cre⁺) mice. These mice develop grossly normal thymic and peripheral T cell subsets. Given the regulation of TET2’s expression and activity by TCR stimulation, we used a murine model of acute viral infection, specifically LCMV-Armstrong, to test if TET2 regulates antigen-specific T cell responses in vivo. Following viral challenge, TET2^fl/flCD4Cre⁺ mice have similar antigen-specific CD8⁺ T cell expansion and effector responses but exhibit significantly enhanced memory CD8⁺ T cell differentiation compared to control mice. These data demonstrate that TET2 plays a critical role in directing CD8⁺ T cell differentiation and function. Studies are ongoing to identify specific TET2 regulated genes important in the development of CD8+ T cell memory.