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Principal Investigator: Houser, Cassandra
Institute Receiving Award University Of Rochester
Location Rochester, NY
Grant Number F31ES032301
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Sep 2021 to 31 Aug 2024
DESCRIPTION (provided by applicant): PROJECT SUMMARY Environmental factors are key modulators of immune function. However, the mechanisms by which immune cells sense environmental cues, and integrate them into specific immune responses are not well understood. The aryl hydrocarbon receptor (AHR) is one means by which environmental signals regulate immune responses. The AHR is a ligand-regulated transcription factor that binds structurally diverse molecules, including certain pollutants, dietary factors, and chemicals from microorganisms. Epidemiological and animal studies demonstrate that AHR-binding compounds alter adaptive immune responses, but the cellular components and governing mechanisms are not fully defined. Changes to CD4+ T cell differentiation and function are among the most consistently observed effects of exposure to ligands of the AHR. We recently discovered that AHR activation alters the percentage and number of T follicular helper cells (Tfh cells) and limits the production of virus-specific antibodies during infection. This is significant because Tfh cells are required for humoral (antibody-mediated) immunity, and environmental exposure to AHR ligands dampens antibody responses. Yet, how the AHR modulates Tfh cells is not known. The proposed studies will test the central hypothesis that the AHR in CD4+ T cells affects Tfh cell differentiation and function. Tfh cell differentiation involves CD4+ T cell activation, differentiation, proliferation, and survival. The AHR could affect these processes singly or in combination to alter Tfh cell differentiation. Thus, in the first aim will we will use lineage-specific Ahr gene ablation, multi-parameter flow cytometry, and enzyme linked immunosorbent assays to determine whether AHR activation alters Tfh cell differentiation by affecting CD4+ T cell activation, proliferation, and/or apoptosis. Additionally, these studies will determine whether changes to Tfh cell differentiation and function are solely due to AHR-driven changes in CD4+ T cells. The second aim will use single cell RNA-seq and ChIP-seq to evaluate AHR regulation of genes in CD4+ T cells that encode factors critical to Tfh cell differentiation. Given that humans exposed to AHR-binding pollutants exhibit greater incidence and severity of infections, as well as reduced antibody responses to common vaccines, these findings will fill key gaps in knowledge and provide necessary data for translational studies with populations exposed to AHR binding chemicals in their environment.
Science Code(s)/Area of Science(s) Primary: 05 - Signal Transduction
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications See publications associated with this Grant.
Program Officer Michael Humble
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