Tet2-mediated programing balances T follicular helper cell and T helper 1 cell differentiation.

Abstract

The differentiation of CD4+ T cell subsets in response to infection has been studied extensively, however the epigenetic programs that regulate these processes remain poorly understood. Active demethylation by tet methylcytosine dioxygenases of CpG dinucleotides within DNA is a key component of epigenetic programing that promotes lineage specific gene expression and contributes to cellular differentiation and function. Here we report that Tet2 acts to restrict the differentiation of T follicular helper (Tfh) cells in CD4+ T cells responding to viral infection. Using an adoptive transfer model of virus-specific CD4+ cells we found that Tet2-deficient CD4+ T cells skew away from the Th1 lineage and instead preferentially differentiate into highly functional germinal center (GC) Tfh cells that provide enhanced help for B cell responses. We found that the impact of Tet2-mediated programing on CD4+ T cell differentiation is cell intrinsic and the shift in lineage differentiation occurs as early as 2 days post infection. Using genome-wide expression, DNA methylation and transcription factor binding analyses, we found that Tet2 coordinates with multiple transcription factors to mediate the demethylation and expression of their target genes following activation. Our findings establish Tet2 as an important regulator of Tfh cell differentiation and reveal pathways that could be targeted to enhance GC responses against infectious disease. Supported by grants from NIH (R01 AI137238 to J.S.H., T32 AI055434 to L.M.S., and T32 AI138945 to A.B.