Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Immunology

Language

English (en)

Date of Award

January 2009

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Kenneth Murphy

Abstract

Activator protein 1: AP-1) transcription factors are dimers of Jun, Fos, musculoaponeurotic fibrosarcoma: MAF) and activating transcription factor: ATF) family proteins that are characterized by a basic region and a leucine zipper domain. While many AP-1 proteins also contain defined transcriptional activation domains: TADs), some consist only of a basic region and leucine zipper and are thought to function as inhibitors of AP-1 activity. We found that the AP-1 protein Batf, which lacks a TAD, is highly expressed in T helper cells compared to various other immune cells and tissues. IL-17-producing T helper: TH17) cells are a CD4+ T cell subset that coordinates inflammatory responses in host defense but are pathogenic in autoimmunity. To study the role of Batf in T cells, we generated Batf deficient mice by gene targeting. Batf -/- mice show a highly selective defect in TH17 differentiation. As a result, Batf -/- mice are completely resistant to experimental autoimmune encephalomyelitis. Using gene expression analysis, we found that Batf -/- T cells fail to induce known TH17-specific transcription factors, such as RORγt, and the cytokine IL-21, required for TH17 differentiation. Neither addition of IL-21 nor overexpression of RORγt fully restores IL-17 production in Batf -/- T cells, suggesting that Batf may be required directly for IL-17 transcription. We found that the IL17 promoter is Batf-responsive, and upon TH17 differentiation, Batf binds to several conserved intergenic elements in the IL17A/F locus as well as to regions in the IL17, IL21 and IL22 promoters. Using bio-computational methods we determined that the Batf-binding element in the IL17, IL21 and IL22 promoters differs from canonical symmetric AP-1 elements. Using EMSA analysis we found that Batf forms heterodimers preferentially with JunB during TH17 differentiation. These results demonstrate that the AP-1 factor Batf regulates previously unknown AP-1 target genes to control TH17 differentiation and TH17-mediated autoimmune disease.

DOI

https://doi.org/10.7936/K7BG2M0C

Comments

Permanent URL: http://dx.doi.org/10.7936/K7BG2M0C

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