All ETDs from UAB

Advisory Committee Chair

Hui Hu

Advisory Committee Members

Robinna G Lorenz

Troy Randall

Casey T Weaver

Amy Weinmann

Document Type

Dissertation

Date of Award

2021

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

High affinity antibody responses rely on the interaction between CD4+ T cells andB cells, but these cell populations are segregated into different regions of secondary lymphoid organs (SLO). Early-stage follicular helper CD4+ T cells (Tfh cells) upregulate the B cell follicle-homing chemokine receptor CXCR5 in order to move from the T cell zone to the B cell follicle and establish interactions with cognate B cells that are essential for T-dependent humoral immune responses. Cognate Tfh and B cell interactions progress to the formation of germinal center (GC) reactions, where B cell receptors undergo rapid evolution to substantially increase antigen recognition affinity. Tfh cells have been proposed to undergo stages of differentiation and can be subdivided into two populations based on the expression of CXCR5, transcription factor Bcl6, and coinhibitory molecule PD-1: 1. PD-1+CXCR5+ CD4+ T cells, located at the T-B cell border and within the follicle mantle zone enclosing the GC. 2. PD-1hiCXCR5hi germinal center Tfh (GC-Tfh) cells, that are located deep in the B cell follicle and provide help to cognate GC B cells. Interestingly, multiple groups have described a follicular helper-like CD4+ T cell memory cell population that expresses both CXCR5 and central memory T cell chemokine receptor CCR7. A fundamental challenge in the Tfh field is how to distinguish the population of PD-1+CXCR5+CD4+ T cells that will differentiate into GC-Tfh cells from the population of follicular helper-like memory precursors/memory cells. This study provides novel insight into the relationships between PD-1+CXCR5+ CD4+ T cells, GC-Tfh cells, and CXCR5+CD4+ memory cells. We found the sustained expression of Tigit is associated with the transition of PD-1+CXCR5+CD4+ T cells to GCTfh cells, whereas loss of Tigit expression is correlates with CXCR5+CD4+ T cell memory generation. Further, we characterize and interrogate a distinct GC-Tfh cell differentiation program at both the transcriptional and chromatin accessibility levels. As a proof of principle, we demonstrated factors Padi4, Gpr132, and Birc5 play a stage specific role in GC-Tfh cell differentiation and/or maintenance. Collectively, this dissertation delineates the relationships between B cell follicle associated CD4+ T cell subsets.

Share

COinS