Biomedical Sciences ETDs

Publication Date

Summer 6-29-2018

Abstract

In this comprehensive project, three interrelated studies with distinct foci were employed to understand the regulations of specific CD4+ T helper cell population in inflammatory diseases.

Pathogenic TH17 cells play an essential role in the initiation and development of both human multiple sclerosis (MS) and animal experimental autoimmune encephalomyelitis (EAE). Nevertheless, the underlying mechanism by which the pathogenicity of TH17 cells is controlled in the autoimmune neuro-inflammation remains unclear. In aim 1, we revealed that lumican (Lum), an extracellular matrix (ECM) protein, negatively regulates encephalitic TH17 cell responses. Our findings highlighted a TH17 cell-intrinsic effect of Lum in suppressing TH17-mediated EAE via promoting TH17 cell apoptosis and diminishing cytokine production.

Obesity is well-characterized as a major risk factor for the development of asthma and recent meta-analysis studies have implicated a positive correlation between serum leptin, an adipokine highly elevated in obese individuals, and the risk of asthma. However, the underlying mechanism whereby obesity-associated elevation of leptin increases the risk of asthma has not been well established. In aim 2, a crucial pathogenic role of leptin in developing TH2 type response-mediated allergic asthma was uncovered. Our findings delineated a novel mechanism whereby leptin promotes pro-allergic lymphocyte responses in activation of the mTOR/MEK-IRE1-XBP1 axis, and thus exacerbating allergic asthma.

Regulatory T (Treg) cells are crucial in maintenance of self-tolerance and immune homeostasis and are implicated as a promising therapy for treating multiple inflammatory diseases. However, the instability of Treg cells presents as a major hurdle for such implementation. Pro-inflammatory cytokine signals are principal factors driving loss of Treg cell identity and dampening Treg cell suppressive function. In aim 3, we found the cytokine suppressor CIS is required for stabilizing Treg cells. This study identified a novel underlying mechanism by which CIS stabilizes Treg cells through antagonizing IL-4-STAT6 signals and maintaining Foxp3 expression.

In summary, these studies provide novel and comprehensive understanding on the regulations of CD4+ T helper lymphocytes in inflammatory diseases. Our findings might suggest novel options for therapeutic applications via targeting Lum, leptin and CIS associated pathways.

Keywords

CD4+ T helper cell, Allergic asthma, Autoimmunity, Inflammation, Leptin, CIS

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Xuexian Yang

Second Committee Member

Judy Cannon

Third Committee Member

Bryce Chackerian

Fourth Committee Member

Bridget Wilson

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