Early Life Exposures and Epigenetic Regulation
Recent research indicates that developmental exposure to pollutants is an overlooked but important contributor to poorer outcomes following viral infection; however, how these early life exposures cause enduring changes in immune function is not clear. Using a model developmental immunotoxicant and influenza A virus as a prototypical human pathogen, we are conducting research to determine precisely how developmental exposures reprogram the offspring's immune system. In these studies, we use developmental exposure to the AHR-specific ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, also called dioxin), which causes long-lasting deficiencies in the offspring's response to influenza A virus infection. Defects include reduced expansion and differentiation of virus-specific CD8+ T cells and impaired production of the antiviral cytokine IFNα. A major goal of our current research efforts is to understand how environmental signals delivered via the AHR during fetal and neonatal development cause long-lasting impairment of CD8+ T cell responses to infection. Although epigenetic mechanisms are known to regulate gene expression in immune cells, the idea that inappropriate AHR activation during development causes permanent functional changes via an epigenetic mechanism is a novel paradigm.
We are determining the contribution of reprogramming in specific hematopoietic lineages using a combination of progenitor cell transplantation, lineage-specific gene ablation, and adoptive transfers identify the developmental and lineage-specific targets of AhR that cause long-lasting reductions in the capacity of CD8+ T cells to respond to infection. To identify gene targets whose expression is differentially silenced or activated by developmental exposure we are defining AhR-mediated changes in CpG methylation and covalent histone modifications at specific immunoregulatory gene loci, and using novel genome-wide approaches to identify additional epigenetically regulated genes that are affected.
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