All ETDs from UAB

Advisory Committee Chair

Casey T Weaver

Advisory Committee Members

Etty Benveniste

Scott R Barnum

Charles O Elson

Robin D Hatton

Louis B Justement

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Autoimmune and autoinflammatory diseases are a collection of disorders that are mediated by reaction of the adaptive immune system against self or commensal antigens. Altered transcription of genes involved in T cell activation and function is a key mediator of predisposition to numerous autoimmune disorders, including Inflammatory Bowel Disease (IBD) and Multiple Sclerosis (MS). However, we have an inadequate understanding of how the transcriptional circuits controlling these genes are dysregulated in disease. Interleukin-10 (IL-10) is cytokine with potent anti-inflammatory activity that is critical for restraining immune-mediated pathology to self-tissues. Notably, patients with nullifying mutations in IL10 develop a severe IBD in the first years of life, and variants in IL10 are associated with several inflammatory disorders. CD4+ T cells are an essential source of Il10 in vivo, and multiple lineages of T cells are capable of expressing Il10. Despite the non-redundant function of IL-10 in preventing autoimmunity, an understanding of the complex transcriptional regulation of Il10 remains incomplete. Here, we identified the transcription factor Growth Factor Independent 1 (Gfi1) as a potent repressor of Il10 transcription in multiple lineages of CD4+ T cells. T cells from mice deficient in Gfi1 produce excess Il10 mRNA and IL-10 protein in vitro, and mice deficient in Gfi1 in the T cell compartment are highly resistant to mouse models of MS and IBD driven by both Th17 and Th1 cells. This reduced disease is dependent upon increased T cell expression of IL-10 in vivo. Mechanistically, Gfi1 bound to the Il10 locus in developing Th17 and Th1 cells, leading to epigenetic repression of Il10 and reduced binding of pioneer transcription factors in the Il10 locus. Genomic analysis of chromatin accessibility found that Gfi1 acts to restrain the activity of activating pioneer factors at critical enhancer elements in Il10 and other T cell genes implicated in autoimmune pathogenesis. Interestingly, the transcription factors antagonized by Gfi1 are distinct between Th17 and Th1 cells, suggesting that Gfi1-mediated repression is integrated into the unique transcription factor circuits present in disparate lineages of T cells. Thus, we have identified a novel transcriptional regulatory mechanism critical in CD4+ T cell-driven inflammation.

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