All ETDs from UAB

Advisory Committee Chair

Andre Ballesteros-Tato

Advisory Committee Members

Laurie Harrington

Craig Maynard

Troy Randall

Hubert Tse

Amy Weinmann

Document Type

Dissertation

Date of Award

2023

Abstract

T follicular helper (Tfh) cells constitute a distinct subset of CD4 T cells that reside within B cell follicles, playing an indispensable role in orchestrating the Germinal Center (GC) response. In response to polarizing environments, such as Influenza A virus infection (IAV), Tfh cells secrete effector cytokines, including IFN-γ and IL-4. Nevertheless, the specific functions of cytokine-producing Tfh cell subsets, beyond their involvement in driving class switch recombination (CSR), remain largely unexplored. Here, we demonstrate that, following IAV infection, Tfh cell cytokine production undergoes a dynamic shift, transitioning from early IFN-γ dominance to later predominance of IL-4. The initial IFN-γ production by Tfh cells influences the GC B cell response, skews cells towards memory B (Bmem) cell differentiation, and thus contributes to the development of lung-memory B cells (lung-BRMs), a specific Bmem population that takes residence in the lungs and rapidly differentiate into antibody-secreting cells (ASC) upon antigen re-encounter. This mechanism accelerates the secondary antibody response in the event of antigen re-exposure. Mechanistically, IFN-γ signaling, sourced from Tfh cells, acts intrinsically on GC B cells, upregulating T-bet and facilitating the generation of CXCR3+ precursor memory B cells (preMems), which serve as precursors to lung-BRMs. Consequently, in the absence of Tfh cells producing IFN-γ, CXCR3+ pre-Mem B cell generation in GC B cells is hindered, ultimately obstructing lung-BRM cell differentiation. Our findings propose a model wherein transient changes in Tfh cell cytokine profiles dynamically influence GC fate decisions during influenza infection, providing novel insights into the determinants of the GC response outcome.

Share

COinS