TET2 Regulates CD4+ T Follicular Helper Differentiation

Abstract

DNA methylation is a key epigenetic mechanism that controls T cell differentiation. The ten-eleven translocation (TET) family of methylcytosine dioxygenases converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and other oxidized methylcytosines. TET2 mutations have been identified in angioimmunoblastic T cell lymphomas (AITL), which are derived from CD4+ T follicular helper (TFH) cells. CD4+ TFH cells are a T cell subset that provides essential help for the germinal center reaction and class switching. Here we demonstrate that TET2 regulates murine CD4+ TFH differentiation in vivo . At steady-state, mice with a T cell specific deletion of TET2 (TET2cKO) have intact thymic and peripheral T cell populations. Following acute viral infection with LCMV-Armstrong, TET2 loss promotes CD4+ TFH cell expansion. Examination of the Peyer's patches (a site of TFH differentiation in response to gut microbes) of wild-type and TET2cKO mice demonstrate an increase in the absolute number of the CD4+ TFH (CXCR5+PD1+) population in TET2cKO mice. Furthermore, there is an increase in the frequency and absolute number of germinal center B cells (characterized by PNA+GL7+ B cells) and an increase in IgA+ B cells in the Peyer's patches of TET2cKO mice compared to wild-type mice. Ongoing studies are examining the mechanism by which TET2 controls CD4+ TFH expansion. Our data indicate that TET2 is an important regulator of CD4+ TFH cells. Understanding the role of TET2 in normal CD4+ TFH differentiation and its contribution to T cell lymphomagenesis will lead to important insights into the epigenetic and molecular mechanisms underlying AITL pathogenesis DisclosuresNo relevant conflicts of interest to declare.