Tet2 coordinates with Foxo1 and Runx1 to balance T follicular helper cell and T helper 1 cell differentiation.

Abstract

In response to various types of infection, naïve CD4⁺ T cells differentiate into diverse helper T cell subsets; however, the epigenetic programs that regulate differentiation in response to viral infection remain poorly understood. Demethylation of CpG dinucleotides by Tet methylcytosine dioxygenases is a key component of epigenetic programing that promotes specific gene expression, cellular differentiation, and function. We report that following viral infection, Tet2-deficient CD4⁺ T cells preferentially differentiate into highly functional germinal center T follicular helper (T_FH) cells that provide enhanced help for B cells. Using genome-wide DNA methylation and transcription factor binding analyses, we find that Tet2 coordinates with multiple transcription factors, including Foxo1 and Runx1, to mediate the demethylation and expression of target genes, including genes encoding repressors of T_FH differentiation. Our findings establish Tet2 as an important regulator of T_FH cell differentiation and reveal pathways that could be targeted to enhance immune responses against infectious disease.