All ETDs from UAB

Advisory Committee Chair

Hui Hu

Advisory Committee Members

Susan L Bellis

Etty N Benveniste

Charles O Elson III

Laurie E Harrington

Craig L Maynard

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

While the exact cause of many autoimmune diseases is currently unknown, many genetic factors are associated with increased disease susceptibility such as single nucleotide polymorphisms in the STAT4 gene locus. Signal Transducer and Activator of Transcription 4 (STAT4) is critical for the development and function of Th1 cells; however, many Th1 associated molecules are dispensable for CD4 mediated inflammation such as IFNγ, T-bet, and IL-12Rβ2, suggesting that STAT4 may function outside of the Th1 cell lineage. Importantly, Stat4 has recently been correlated with an inflammatory Th17 cell phenotype. Using a murine model of neuroinflammation, we illustrate that Th17 intrinsic STAT4 influences pathogenic gene expression, cell migration molecules and cell metabolism to drive neuroinflammation. We also find an inverse relationship between STAT4 and IL-10 when naïve CD4 T cells are exposed to Th17 differentiation conditions in vitro. Furthermore, we find that this inverse STAT4/IL-10 interaction plays a key role in mediating intestinal inflammation in that STAT4 drives CD4 T cell pathogenicity by diminishing IL-10 production. Due to previously identified functions of STAT4, we do not postulate that STAT4 is directly interacting with Il10, and our data indicate that Blimp1 and c-Maf may be intermediate molecules. While there are many disease modifying therapies for autoimmune diseases, most of these are non-specific, thus leaving the patient iv immunocompromised. Data described in this dissertation illuminate a novel pathogenic role for STAT4 in CD4 T cell mediated inflammatory diseases. Findings from these studies can be used to develop future therapeutic options for patients struggling with autoimmune disease.

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