| Description |
In response to viral infection, CD4+ helper T cells provide critical signals to provide help for B cell and CD8+ cytolytic T cell responses that can help eliminate the infectious pathogen. However, during chronic viral infections, persistent antigen results in T cell exhaustion, which is characterized by decreased functionality and survival. While T cell exhaustion is well-characterized for CD8 T cells, the determinants of CD4+ T cell functionality during chronic infection are not well defined. As T cells respond to infection, they undergo epigenetic DNA methylation programming that dictates which genes are permissive to transcription during viral infections. DNA methyltransferase 3a (DNMT3a) is responsible for de novo methylation of CpG sites on regulatory elements that blocks transcription and expression of these genes. In contrast, the enzyme Ten-eleven translocase 2 (TET2) catalyzes the active de-methylation of CpG sites so that the genes can be expressed. While it is known that Dnmt3a plays a role in promoting CD8 T cell exhaustion, it is not known whether Tet2 and Dnmt3a regulate CD4+ T cell programming and function during chronic infection. This thesis explores the role of DNMT3a and Tet2 in CD4 T cells during chronic infection. Our findings suggest that cell-intrinsic deficiency of DNMT3a in virus-specific CD4+ T cells results in an increased capacity to produce antiviral cytokines, such as IFNγ. In addition, our data suggest that simultaneous loss of DNMT3a and TET2 during chronic viral infection leads to hyper-proliferation and survival of virus-specific CD4+ T iv cells which can provide help to improve the functionality of wild-type exhausted antigen-specific CD8+ T cells. Together these findings demonstrate that Dnmt3a and Tet2 mediated programming regulates the function and differentiation of CD4+ T cells during chronic infection. This has important implications for enhancing T cell responses to chronic antigens and understanding cell regulation in T cell lymphomas. |
