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Differential Mechanisms Underlying Inflammatory Th17 Cells in Autoimmunity and Colitogenic Infection

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title
Differential Mechanisms Underlying Inflammatory Th17 Cells in Autoimmunity and Colitogenic Infection
author
Bouch, Ronald Jacob
abstract
Th17 cells are a heterogeneous population that are critical for tissue homeostasis and inflammation during clearance of infections and autoimmunity. Substantial efforts have been made to characterize the homeostatic and inflammatory roles of Th17 cells and as a result, partially-effective therapeutic strategies are available for a variety of autoimmune indications. However, the mechanisms which underlie the divergent functions of inflammatory Th17 cells during autoimmune and colitogenic infections remain largely unexplored. These ill-defined mechanisms are the sole attributors to the lack of selectivity of modern therapeutics leading to the detrimental, frequently fatal, immunocompromising side effects. In this study, we demonstrate that inflammatory Th17 cells engaged in autoimmune colitis and those involved in the resolution of C. rodentium infection are two distinguishable populations illustrated by their distinct phenotypic responses to the pharmacological small-molecule, clofazimine (CLF). CLF selectively inhibits autoimmune Th17 cells via suppression of pro-inflammatory cytokines while preserving the functional state of infection-elicited Th17 cells. Our report of the unique selectivity of CLF on inflammatory Th17 cells is a novel finding. Thus, we sought to use CLF to investigate the impacted pathways and their implications in the differential inflammatory function in autoimmunity and infection-response. T cell effectors are highly dependent on and programmable through metabolic changes during pro-inflammatory conditions. To understand the influence of metabolism on Th17 function in autoimmunity, we explored the metabolic response of inflammatory Th17 cells to CLF. Through the reduced expression of mitochondrial enzyme ALDH1L2 and subsequently the elevation of intracellular serine levels, we show that inflammatory Th17 cells in autoimmune colitis selectively require serine metabolism to promote autoimmune inflammation and pathology whilst being dispensable for inflammation to resolve C. rodentium infection. The transcriptional regulation of effector function is likely explained by increased levels of DNA methylation and repressive histone tri-methylation, a metabolic response directly linked to perturbed serine metabolism. Collectively, our data suggests that autoimmune Th17 and infection-elicited Th17 cells are two distinguishable subsets with unique regulatory mechanisms, indicating the feasibility of targeting inflammatory Th17 cells in autoimmunity with a higher degree of selectivity.
subject
Autoimmunity
Clofazimine
Inflammatory Th17 Cells
Mucosal Immunity
Serine Metabolism
contributor
He, Zhiheng (advisor)
Soto-Pantoja, David (committee member)
Alexander-Miller, Martha (committee member)
Grayson, Jason (committee member)
Haas, Karen (committee member)
date
2023-09-08T08:35:24Z (accessioned)
2023 (issued)
degree
Microbiology & Immunology (discipline)
embargo
2025-09-07 (terms)
2025-09-07 (liftdate)
identifier
http://hdl.handle.net/10339/102616 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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