All ETDs from UAB

Advisory Committee Chair

Casey T Weaver

Advisory Committee Members

David D Chaplin

Randy Q Cron

Louis B Justement

Robinna G Lorenz

Thomas M Ryan

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Protective immunity against a variety of infections depends on the amplification and differentiation of naïve antigen-specific CD4 T cells. T helper 17 (Th17) cells are important for defending mucosal barriers from invading extracellular bacterial pathogens. This effector CD4 lineage is characterized by production of the cytokines IL-17A, IL-17F, IL-21, and IL-22, which elicit influx of inflammatory cells to promote pathogen clearance. The cytokines IL-6 and TGF&beta are the principal factors that initiate Th17 lineage development, and the STAT3-inducing cytokines IL-21 and IL-23 assist and/or maintain the Th17 developmental program. Recently, an additional cytokine has been demonstrated to encourage Th17 differentiation: IL-1&beta. IL-1&beta impacts expression of Th17-associated genes very early in the course of Th17 lineage commitment, and in combination with IL-6 or IL-23, it can induce robust TCR-independent IL-17 production. However, the mechanism(s) by which IL-1&beta exerts these effects are poorly understood. We have examined the effects of IL-1 signaling upon Th17 chromatin conformation and transcription factor recruitment. We found that IL-1&beta induces activation of NF-&kappaB proteins that bind critical genomic regulatory elements to affect Il17 transcription. Our data suggest that IL-1&beta also modifies chromatin architecture, as its presence allowed for enhanced binding of the crucial Th17 transcription factor STAT3 to regulatory sites in the extended Il17a/f locus. Additionally, IL-1&beta impacts proximal signaling events that result in amplification of STAT activation in response to cytokine signals in microenvironment. All of these mechanisms augment the ability of Th17 cells to respond effectively to pathogens and aid in host defense. The long held belief that T helper cell differentiation results in irreversible lineage commitment with permanent heritable accessibility or silencing of cytokine genes has been undermined by recent studies demonstrating plasticity of helper T cell phenotypes. We demonstrate that epigenetic instability at the Ifng, Il17a/f, and Rorc cytokine gene loci underlie the propensity of Th17 cells to convert to IFN-&gamma-producing cells under conditions of limited TGF-&beta. This plasticity illustrates the dynamic interplay of transcription factors and epigenetic modifications that occur at cytokine gene loci in response to cytokine signals, which are of profound consequence for host defense.

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