All ETDs from UAB

Advisory Committee Chair

Laurie E Harrington

Advisory Committee Members

Etty Benveniste

Charles Elson

Claude Steele

Alexander Szalai

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Multiple Sclerosis (MS) is an autoimmune disease whereby the host immune system fails to recognize self vs non-self and targets myelin of the central nervous system. Currently there is no permanent cure for MS and the efficacy of immune modulatory treatments often wane over time, therefore we seek to determine novel pathogenic mechanisms to target therapeutically. CD4 T cells have been found within inflammatory CNS lesions of MS patients and are believed to be important mediators of MS pathology. To study CD4 T cells in the context of MS, we use the well-defined MS mouse model experimental autoimmune encephalomyelitis (EAE). EAE has demonstrated a critical role for Th1 and Th17 CD4 T cells, however, how these T cell subsets drive disease remain unknown. STAT4 is a Th1 transcription factor that is activated by IL-12, which results in the production of the signature Th1 cytokine IFN gamma;. Interestingly, while STAT4 is required for EAE, IL-12 and IFN gamma; are dispensable raising the question of how STAT4 is modulating disease independent of the prototypic IL-12 signaling pathway. Th17 CD4 T cells have been shown to develop independently of STAT4, and it is unclear why these cells are unable to drive pathogenesis, suggesting that STAT4 regulates not only Th1, but also Th17 pathogenicity during EAE. Herein we describe two novel observations on the contribution to STAT4 during EAE pathogenesis. First, GM-CSF is critical for EAE and produced by both Th1 and Th17 cells and it remains unknown how STAT4 regulates this process. We find that STAT4 regulates T cell intrinsic expression of GM-CSF during EAE and is a result of direct interaction of STAT4 with the GM-CSF gene, Csf2. Secondly, the contribution of STAT4 to CD4 T cell accumulation during EAE has not been explored. We determine that CD4 T cell intrinsic STAT4 expression regulates both early and peak T cell accumulation during EAE. Furthermore, STAT4 mediate Th17 driven disease and CD4 T cell accumulation during the early stage. These studies highlight several unexplored facets of STAT4 in the context of EAE and highlight a previously unrecognized role of STAT4 in mediating Th17 disease.

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