UC San Diego

The Erk (Extracellular signal-regulated protein kinase) signaling pathway is thought to be critical for T cell survival, proliferation and differentiation. However, the role of Erk in Th1 and Th2 differentiation is controversial. Most of the previously published studies used a MEK inhibitor to examine the function of Erk in CD4 T helper cell and induced regulatory T cell differentiation; yet the role of Erk2 and its distinction from Erk1 in CD4 T effectors and regulatory cells remains unclear. In this study, we used germline Erk1 knockout mice and tamoxifen-regulated conditional Erk2 knockout mice to identify the role of these two major Erk isoforms within mature CD4 T cells. In vitro studies have revealed that Erk1 is dispensable for most aspects of CD4 T cell activation, while Erk2 performs several non-redundant functions. In the scope of this research project, we observed that Erk2 supported early CD4 T cell proliferation, as well as the differentiation of Th1, but not Th2 or Th17 cells. In addition, virus-specific Th1 responses in the absence of Erk2 were greatly impaired, Furthermore, the reduction in Erk2 signaling enhanced induced regulatory T cell (iTreg) function in vitro and in vivo. Both Erk1-/- and Erk2-/- nature regulatory T cells can suppress CD4 T cell proliferation similar to wild type. In addition, when compared to wild type T cells, we observed down-regulated DNA methyltransferase (DNMT), and increased phospho-Smad2/3 in Erk2-/- CD4 T cells cultured under iTreg conditions. We hypothesized that this decrease in DNMT and increase in TGFbeta signing is induced by an increase in Foxp3 expression. In summary, this study demonstrates that Erk2 plays an important role in CD4 T cell proliferation and differentiation in vitro and in vivo