Aryl hydrocarbon receptor regulation of T follicular helper cells during respiratory viral infection

• Published in: The Journal of immunology (1950) 2021-05, Vol.206 (1_Supplement), p.24-24.02
• Main Author: Houser, Cassandra L
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.206.Supp.24.02

The aryl hydrocarbon receptor (AHR) is a ligand-regulated transcription factor that binds structurally diverse molecules from the environment, including pollutants, dietary factors, and chemicals from microorganisms. AHR-binding compounds alter adaptive immune responses, but the cellular components affected and governing mechanisms are not fully defined. For instance, AHR activation affects antibody responses; a process for which T follicular helper cells (Tfh cells) are critical. We recently discovered that AHR activation alters the percentage and number of Tfh cells during influenza A virus (IAV) infection. Yet, how the AHR modulates Tfh cells is not known. The present work shows that AHR-mediated changes to Tfh cells are due to changes in CD4+ T cell proliferation and BCL6 expression, an essential transcription factor for Tfh cell differentiation. Utilizing conditional AHR knockout mice, we show that changes to Tfh cells require AHR expression in CD4+ T cells. The AHR regulates gene expression directly, via its DNA-binding domain (DBD), and indirectly via other signaling molecules. To delineate which pathways it uses to modulate Tfh cells, we used mice with a mutated AHR DBD and demonstrate that it requires its cognate DBD to regulate Tfh cells during infection. This supports that AHR modulates Tfh cells by directly regulating gene expression. Overall, these findings provide new information about how AHR signaling influences humoral immunity to a common respiratory pathogen. Given that exposure to AHR-binding pollutants impacts immune responses to infections and vaccines, better understanding of the mechanisms that control Tfh cell responses has broad reaching impact on immune defenses and immune-mediated diseases.