[PhD Thesis Presentation_Zoom] ‐ Tsung-Han Hsieh – Deciphering the role of AP-1 transcription factor JunB in CD4+ T cells
Presenter: Tsung-Han Hsieh
Supervisor: Prof. Hiroki Ishikawa
Unit: Immune Signal Unit
Title: Deciphering the role of AP-1 transcription factor JunB in CD4+ T cells
Differentiation of distinct CD4+ T effector cell subsets is a key event for adaptive immune responses. Upon recognition of antigens, naïve CD4+ T cells differentiate into functionally distinct CD4+ effector T cell subsets, which control different types of adaptive immunity. The differentiation of CD4+ T effector cells is regulated by the BATF-containing AP-1 heterodimers and their associating proteins IRF4, BATF and IRF4 are induced by T cell receptor (TCR) and co-stimulatory signals and regulate expression of genes required for a broad spectrum of biological functions across diverse CD4+ effector T cell subsets. These transcription factors have been shown to be essential for lineage specification, metabolic activity, and survival of various CD4+ effector T cell subsets, including T helper 1 (Th1), Th2, Th9, Th17, follicular T helper (Tfh) and effector regulator T (eTreg) cells. In contrast to IRF4 and BATF, the role of the major BATF-heterodimeric partner, JunB, in CD4+ T cell differentiation is still not fully understood. In this thesis, I demonstrate that JunB promotes the survival of TCR-stimulated CD4+ T cells under Th1-, Th2-, and Th17-polarizing conditions. Consistent with this, accumulation of antigen-primed JunB-deficient CD4+ T cells are dramatically impaired in mice immunized with complete Freund’s adjuvant (CFA), LPS, or papain. RNA-sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analyses reveal that JunB directly regulates expression of various genes that are commonly induced in priming of naïve CD4+ T cells, including a pro-apoptotic gene Bcl2l11 (encoding Bim), and genes that are specifically induced in Th1, Th2, and Th17 cells. Furthermore, JunB colocalizes with BATF and IRF4 at genomic regions for more than 70% of JunB direct responsive genes. Taken together, JunB, in collaboration with BATF and IRF4, serves a critical function in differentiation of diverse CD4+ T cells by controlling common and lineage-specific gene expression.