Regulation of TH17 Cells during Inflammatory Disorders

Date of Award

Spring 2022

Document Type


Degree Name

Doctor of Philosophy (PhD)



First Advisor

Flavell, Richard


A balance between immunity against pathogens and tolerance to non-harmful stimuli is carefully maintained by our immune system under homeostatic conditions. Effector CD4+ T cells, particularly TH17 cells, are one of the major immune cell types that surveil mucosal homeostasis by producing pro-inflammatory cytokines, including IL-17A and IFN. However, when the immune balance is disrupted, massive numbers of TH17 cells infiltrate different tissues and organs, leading to a series of inflammatory disorders, such as inflammatory bowel diseases (IBDs) and multiple sclerosis (MS). Therefore, TH17 cells must be carefully monitored by multiple regulatory machineries, which are compromised or overridden by other stimuli during chronic inflammation. Here we show that during inflammatory disorders, TH17 cells are regulated at least from 3 different levels: 1) Microbial metabolites, as environmental cues, regulate TH17 differentiation and intestinal inflammation; 2) Extracellular lipids, as host-intrinsic factors, control TH17 pro-inflammatory cytokine expression and CNS inflammation; 3) TGF-β signaling pathway, as cell-intrinsic program, directs TH17 plasticity towards a regulatory phenotype.In the first part of this study, we identified that A. intestini, a commensal bacterium isolated from fecal samples of IBD patients, is able to promote TH17 differentiation and thus contribute to intestinal inflammation. Mechanistically, A. intestini produces high levels of butyrate metabolite, which is responsible for elevating IL-17 expression and inducing a TH17-dependent colitis phenotype in mouse IBD models. In the second part of this study, we revealed that LDLR-deficiency or lipid deprivation significantly impairs IL-17 expression and TH17 development. Lipidomics and transcriptomics analysis indicate that LDLR-deficient TH17 cells have abnormal lipid accumulation, which is a consequence of over-activation in de novo lipid biosynthesis programs. Excess cellular lipids disrupt the translation of pro-inflammatory cytokines and as a result, LDLR-deficient mice showed resistance against TH17-mediated CNS inflammation. In the third part of this study, we claim that TGF-β, signaling through SMAD3 and SMAD4, controls the regulatory fate of TH17 cells by promoting IL-10 expression. Disruption in either IL-10 per se, or TGF-β signaling leads to compromised immune homeostasis or impaired resolution of tissue inflammation at intestinal barrier. We also showed for the first time that human TH17 cells gain the expression of IL-10 in response to TGF-β, suggesting their potentials in acquiring an anti-inflammatory function. Taken together, this work dissects multiple mechanisms involved in regulating TH17 differentiation and function, which expands our knowledge in TH17 biology and proposes new way in which anti-inflammatory therapies are designed.

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