All ETDs from UAB

Advisory Committee Chair

Laurie E Harrington

Advisory Committee Members

Etty Benveniste

Charles Elson

John Mountz

Chander Raman

Laura Timeras

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Multiple Sclerosis (MS) is an autoimmune disease resulting from aberrant immune cells causing demyelination. We utilize the well-studied mouse model, experimental autoimmune encephalomyelitis (EAE), to decipher the underlying pathogenesis of MS. Effector CD4 T-cells play a critical role during EAE because the disease is induced by adoptively transferring myelin-specific CD4 T-cells into naïve mice. Classically, effector CD4 T-cells have been divided into distinct subsets based on their functional properties: Th1 cells produce IFNγ, Th2 cells secrete IL-4, IL-5, and IL-13, Th17 cells make IL-17A, IL-17F, IL-21, and IL-22, and regulatory T cells produce IL-10. Th1 cells were originally identified as pathogenic during EAE resulting from reports of Tbet or STAT4 deficient mice being resistant to disease. The recently discovered Th17 cells are also essential to drive EAE since mice that lack RORγt, STAT3, IL-23p19, IL-23R, or IL-6 are protective from disease. However, the functions of both Th1 and Th17 cytokines such as IFNγ and IL-17A/F, respectively, remain controversial. Therefore, we are interested in studying the complexity of CD4 T-cell functions during EAE by investigating the regulation of Tbet in relation to Th1 and Th17 development during disease. We observed a preferential up-regulation of Tbet by CD4 T-cells within the CNS and the IFNγ/IL-17A double producing CD4 T-cells co-express Tbet. In addition, we discovered that the conventional Th1-inducing factors including IFNγ, STAT1, and IL-12 are not required for Tbet up-regulation in CD4 T-cells. Moreover, IFNγ and IL-12 signaling do not have compensatory effects for Tbet expression during disease. To identify the function of Tbet during disease, we generated mixed bone marrow chimeras and identified elevated IL-17A production in Tbet deficient CD4 T-cells, suggesting Tbet intrinsically suppresses IL-17A. Moreover, IFNγR deficient CD4 T-cells expressed augmented IL-17A and normal levels of Tbet, indicating IFNγ represses IL-17A independent of Tbet. We further demonstrated that IFNγ signals through STAT1 to suppress Th17 because IFNγ loses its suppressive effect in STAT1 deficient CD4 T-cells. The Th17 suppression by STAT1 correlates with the gene accessibility of Th17-related loci. These data may provide further insights into Th1 and Th17 development and, more importantly, potential therapeutic targets for MS.



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