Advisory Committee Chair
Laurie E Harrington
Advisory Committee Members
Charles O Elson
Robinna G Lorenz
Amy S Weinmann
Hubert M Tse
Document Type
Dissertation
Date of Award
2018
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Effector CD4 T cells are essential for the balance between pro- and anti-inflammatory immune responses during homeostasis. Dysregulation of effector CD4 T cell responses results in chronic inflammatory disorders such as Inflammatory Bowel Disease (IBD) and Multiple Sclerosis (MS), however therapeutic options for these diseases are limited. Understanding the mechanisms that regulate pathogenicity of effector CD4 T cells is critical to devise new therapeutic interventions. Herein we show two different mechanisms that profoundly impact pathogenic potential of CD4 T cells by regulating heterogeneities of effector functions and differentiation states. Different subsets of effector CD4 T cells utilize distinct metabolic pathways. We find that Th17 differentiation occurs in conjunction with a robust increase of ATP-linked mitochondrial respiration, which fuels energy demand. Interestingly, mitochondrial oxidative phosphorylation (OXPHOS) also supports a transcriptional programing of Th17 development, while suppressing regulatory T cell (Treg) generation. Accordingly, OXPHOS inhibition during Th17 differentiation results in functionally suppressive Tregs and ablates Th17 pathogenicity in a mouse model of MS. Mechanistically, ATP-linked OXPHOS promotes Th17-specific molecular events: BATF induction and STAT3 phosphorylation. In addition, overexpression of BATF rescues Th17 differentiation under OXPHOS inhibited conditions, consistent with that mitochondrial respiration controls Th17 lineage commitment in a BATF dependent manner. Finally, we show that BATF induction is partially regulated by mTORC1 activation, which relies on ATP-linked OXPHOS. Together, our data suggest that mitochondrial respiration is required for pathogenicity of Th17 cells and also controls the Th17 and Treg fate decision. We also find that the differentiation state of CD4 T cells contributes to pathogenicity. A transcriptome analysis of effector CD4 T cells from chronic intestinal inflammation reveals that CD4 T cells exist as a spectrum of differentiation states from stem-like to terminally differentiated. Although both populations of CD4 T cells possess pro-inflammatory effector functions, only CD4 T cells with progenitor potential can confer disease upon transfer and sustain chronicity of inflammation with enhanced survival. In addition, these stem-like CD4 T cells serve as progenitors to the terminally differentiated, IFNγ-producing cells in the inflamed intestine. Superimposition of stem-like gene signatures and the transcriptome of CD4 T cells with progenitor potential show a selective intersection of a gene encoding a glycosyltransferase, ST6Gal-I. Interestingly, ST6Gal-I is required for optimal expression of the stemness-associated transcription factor, TCF1. Our findings indicate that a subset of stem-like effector CD4 T cells preserves the chronicity of T cell mediated inflammation, and cell surface glycosylation impacts on differentiation program and survival of CD4 T cells.
Recommended Citation
Shin, Boyoung, "Regulation Of Effector Cd4 T Cell Pathogenicity During Chronic Inflammation" (2018). All ETDs from UAB. 2959.
https://digitalcommons.library.uab.edu/etd-collection/2959