Advisory Committee Chair
Laurie F Harrington
Advisory Committee Members
Charles O Elson III
Sonya Heath
Hui Hu
Olaf Kutsch
Alexander Rosenberg
Document Type
Dissertation
Date of Award
2023
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
CD4+ T cells regulate the humoral and cellular immune responses by differentiating into T follicular helper (Tfh) cells or into non-Tfh effector cells. Non-Tfh effector cells leave the lymph node and migrate to the effector site whereas Tfh cells upregulate CXCR5 and migrate towards the B cell follicle. The mechanism of CXCR5 induction, however, is still incompletely understood. The transcription factor Bach2 was shown to inhibit the in vitro differentiation of Th1, Th2, and Th17 cells as well as the in vivo Tfh responses. Though, it is unknown how Bach2 arbitrates Tfh and non-Tfh differentiation in vivo. Here, we report that the transient upregulation of transcription factor Bach2 after T cell receptor stimulation plays an important role CXCR5 regulation and CD4+ cell differentiation in vivo. Interestingly, Bach2 was upregulated under Th17 conditions in vitro, and in the absence of Bach2, Th17 cells induced CXCR5 expression. The CXCR5 expression was not dependent on IL-17 expression or RORγt, but rather it was dependent on STAT3 and SMAD signaling downstream of IL-6 and TGF-β. Mechanistically, IL-6/STAT3 drove Cxcr5 promoter activity via the upstream site 1 regulatory element, while TGF-β enhanced permissive histone modifications, and the STAT3 binding to the site 1 regulatory element was higher in the absence of Bach2. In an intraperitoneal immunization system, where notable CD25 expression was not observed, Bach2 inhibited Tfh responses and thereby surprisingly promoted Th17 responses. iv However, in the draining medLN in an intranasal (IN) immunization system, we observed that IL-2 and CD25 were strongly upregulated in the majority of activated cells. STAT5 was also activated and was required for the optimal responses of Tfh and non-Tfh cells. Bach2 inhibited the CD25 expression and blocked the STAT5 signaling from inhibiting CXCR5. In this setting, therefore, Bach2 was indirectly promoting Tfh responses. Concurrently, in the non-draining lymph node after IN immunization, IL-2 and CD25 were not induced and Bach2 again inhibited Tfh responses. Our findings demonstrate that Bach2 plays a complex role in coordinating both the humoral and cellular arms of the immune response.
Recommended Citation
Schroeder, Andrew Ray, "Transcriptional Regulation in Early Stage CD4+ T Cell Activation and Differentiation" (2023). All ETDs from UAB. 376.
https://digitalcommons.library.uab.edu/etd-collection/376