All ETDs from UAB

Advisory Committee Chair

Amy S Weinmann

Advisory Committee Members

Andre Ballesteros-Tato

Laurie E Harrington

John F Kearney

Frances E Lund

Document Type

Dissertation

Date of Award

2021

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Viral infections remain a major cause of morbidity and mortality. Within a viral, interferon (IFN)-ɣ-driven inflammatory microenvironment, B cells may produce antibody which is critical for rapid viral clearance and continued protection from reinfection. However, the roles of IFN-ɣ and IFN-ɣ-induced transcription factors (TFs) in driving antibody secreting cell (ASC) development from their B cell precursors are poorly understood. Herein, we identify two IFN-ɣ-inducible transcription factors (TFs), T-bet and interferon regulatory factor 1 (IRF1), that are essential for the differentiation of ASCs from IFN-g-activated B cell precursors. T-bet repressed an IFN-ɣ-inducible inflammatory gene program that was incompatible with ASC formation in vitro. In contrast, IRF1 is required for dampening BCR signaling thus supporting development of a marginal zone innate-like ASC precursor. Both, T-bet and IRF1, contribute to protective antigen-specific antibody responses upon influenza infection. While B cell-intrinsic T-bet was required for the generation of long-lived ASCs upon viral infection, B cell-intrinsic IRF1 was indispensable for the development of early antigen-specific IgM in response to both viral infection and bacterial immunization. Lastly, we find that immunization with an intranasal Ad5COVID vaccine induces local IFN-ɣ producing T cell responses and the production of durable receptor binding (RBD) specific antibody. Thus, IFN-ɣ and IFN-ɣ-inducible TFs are essential for generating protective humoral immunity.

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