BATF Regulation of Nfil3, Wnt10a, and miR155hg during Lymphocyte Activation Critical for T Cell Differentiation and Antibody Class Switch Recombination
Date of Award
Doctor of Philosophy (PhD)
Committee Member 1
Committee Member 2
Committee Member 3
B cell activating transcription factor (BATF), an immune specific AP-1 transcription factor, functions together with IRF4 and JUNB to regulate genes important for antibody class switch recombination (CSR) in B cells and for the functional differentiation of distinct CD4+T helper (Th) subsets, including Th2, Th9, Th17 and T follicular helper cells. At the time this work was initiated, the expression of BATF in T cells and B cells was known to be critical to the host response to antigen and for the production of class switched immunoglobulins, yet the precise details of how BATF functioned in those roles was unknown. I have demonstrated that BATF expression is increased rapidly, and transiently, immediately following B cell stimulation and I have generated an inducible mouse model of Batf deletion (Izt mice) to show that BATF induction is necessary and sufficient, to trigger the program of CSR. My studies identified two genes (Nfil3 and miR155gh) that are positively regulated by BATF and one gene (Wnt10a) that is negatively regulated by BATF following B cell activation. The molecules encoded by all three of these BATF targets play essential roles in CSR and my studies have shown that each influences the expression and/or function of one other. In addition, I generated a conditional T cell knockout mouse (Tzt mice) in which the Batf alleles are deleted at the double positive stage of T cell development in the thymus. Using Tzt T cells, a cell-intrinsic role for BATF was demonstrated in the differentiation of several CD4+ Th cell lineages. Interestingly, the target genes identified as regulated by BATF in B cells are regulated by BATF in CD4+ Th cells and the products of these genes are required for the normal development of Th2, Th17, and Tfh cells. Manipulating the re-expression of BATF, NFIL3, WNT10A and miR155 through retroviral rescue experiments allowed for the positioning of these molecules in an interactive network downstream of BATF induction and upstream of the terminal events of CSR in B cells and cytokine secretion in differentiated Th2, Th17, and Tfh cells. In conclusion, this work has demonstrated a required role for BATF early in the activation of both B and T lymphocytes, identified genes whose expression depends upon BATF and extends knowledge of the molecular network controlling antibody CSR and Th cell differentiation.
Morman, Rosemary E., "BATF Regulation of Nfil3, Wnt10a, and miR155hg during Lymphocyte Activation Critical for T Cell Differentiation and Antibody Class Switch Recombination" (2018). Open Access Dissertations. 1776.