All ETDs from UAB

Advisory Committee Chair

Allan J Zajac

Advisory Committee Members

Charles O Elson III

Paul Goepfert

Peter J Mannon

Craig L Maynard

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The incidence of inflammatory bowel diseases (IBD) is increasing worldwide. Crohn’s disease (CD) and Ulcerative colitis (UC), the two main subtypes of IBD, are chronic intestinal conditions driven by CD4+ T-cell inflammatory responses to commensal antigen. Both conditions are incurable, and medical treatments involve drugs that require long-term usage but have limited efficacy and significant side effects. To develop therapies targeting the antigen-reactive T cells involved in sustaining these conditions, we must first gain knowledge concerning the microbial antigen-reactive T cell phenotypes and functionality in health and disease. To investigate the phenotypic and functional characteristics of the flagellin-reactive T cell repertoire in Crohn’s disease, the CD154 magnetic enrichment method was optimized. We analyzed peripheral blood CD4+ T cells exposed to single flagellins (CBir1, A4 Fla2, or FlaX) for expression of surface and intracellular markers associated with immune activation, costimulation, and cellular functional properties. Our studies revealed that single flagellin activated total CD4 T cells produced a heterogenous response suggesting only certain activated CD4 cells confer pathogenic effects. We then tested the hypothesis that a limited set of immunodominant microbial antigens, identified by aberrant serologic responses, activate antigen-reactive T cells to disrupt the gut epithelium. Non-IBD healthy, CD and UC patients were assessed for B cell and CD4+ T cell responses to flagellin antigens. We also measured the effects of active CD flagellin-specific cells on epithelial barrier function. CD patient flagellin-specific iv CD154+CD4+ T cells displayed distinct T helper type 1 (Th1) and Th17 effector memory T cells (TEM) and Th1 central memory T cell (TCM) phenotypes. Furthermore, we found a positive correlation between the frequency of flagellin-specific CD154+CD4+ TEM cells and the levels of serum anti-flagellin immunoglobulin G (IgG) in CD patients. In addition, flagellin-reactive T cells from active CD patients produced factors that can directly induce damage to the gut epithelium. Our findings suggest a pathophysiological significance of CD4+ TEM cells in the progression of CD and imply that targeting these cells could be therapeutically valuable.

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