T helper 17 (Th17) cells are a unique CD4+ T cell subset that provides protection against a number of extracellular bacteria, including Streptococcus pyogenes (Sp), Streptococcus pneumoniae, Klebsiella pneumoniae, and Bordetella pertussis. Th17 cells promote protection by secreting cytokines, like IL-17A, that drive trafficking of neutrophils to the site of infection to kill bacteria. A comprehensive network of positive and negative regulators control the Th17 program. While these regulators are known, there is a major knowledge gap of the molecular mechanisms that control the expression of these regulators to establish a pro-Th17 balance. We have recently found a role for Bcl-6 interacting corepressor (BCOR)-mediated repression in driving Th17 differentiation. This grant will elucidate how BCOR influences the expression of known Th17 regulators. The hypothesis of this proposal is that BCOR is recruited by Interferon Regulatory Factor 8 (IRF8) to directly repress negative Th17 regulators, thereby leading to enhanced Th17 differentiation.
Specific Aims : 1) Identify BCOR- and IRF8-specific genomic target sites and determine the influence of BCOR-mediated repression on negative Th17 regulators; 2) Determine whether IRF8 recruits BCOR and drives Th17 differentiation in vivo. Study Design: Immunoprecipitation (IP) and chromatin IP sequencing (ChIP-Seq) techniques will be implemented to determine whether BCOR and IRF8 interact during Th17 differentiation and the genomic target sites that they co-bind. Wild type mice and mice with BCOR-deficient T cells will be infected with Sp and RNA sequencing will be conducted on Sp-specific CD4+ T cells. RNA sequencing will be analyzed with the ChIP-Seq data to determine functional target sites that BCOR both binds and represses. Potential Impact: Vaccine-induced immunity against Sp and S. pneumoniae requires IL-17A and is independent of antibody production. This research will elucidate a novel mechanism by which BCOR-mediated repression in CD4+ T cells drives the generation of IL-17A-secreting Th17 cells. Better understanding Th17 cell differentiation will assist in Th17-focused vaccine development, providing critical cell mediated immunity against extracellular bacteria
Vaccine-induced immunity against Streptococcus pyogenes (Sp) in mice requires the cytokine IL-17A and is independent of antibody production. This proposal will elucidate a novel mechanism by which Bcl-6 interacting corepressor drives the generation of IL-17A-secreting Th17 cells, which are known to provide critical cell mediated immunity against extracellular bacteria. Better understanding the drivers of Th17 cells will inform the development of a Th17-focused Sp vaccine for humans, which is currently unavailable.
