Regulation of Th2 cell function by the tissue milieu

Monday, November 4, 2024 at 12 PM EST

Oliver Harrison, PhD
Assistant Member, Benaroya Research Institute
Affiliate Assistant Professor, Immunology, University of Washington, Seattle

ABSTRACT:

T helper 2 cells must both sense, and adapt to, pathogen and host-derived ligands in order to promote host immunity and tissue repair. Importantly, as Th2 cells traffic from lymph nodes to inflamed tissues, they license IL-13 production selectively within parenchymal tissues to initiate remodeling of the mucosal epithelium. The environmental cues and cell-intrinsic factors that license Th2 cells to produce IL-13 in inflamed tissues are not well understood. Here, we have identified hypoxia, and the oxygen-regulated transcription factor Hypoxia-Inducible Factor 2a (HIF2a), as important drivers of Th2 cell differentiation and IL-13 expression in T cells. We demonstrate that a hypoxic tissue milieu, or genetic activation of HIF2a, function to bolster Th2 cell differentiation in a manner dependent upon elevated autocrine production of IL-4. In vivo, HIF2a is essential for functional Th2 cell responses within the intestinal lamina propria; mice with T cell-specific deletion of HIF2a do not generate protective immunity upon infection and challenge with the intestinal pathogen, Heligmosomoides polygyrus. Our data highlight an unappreciated role for tissue hypoxia as an environmental signal licensing Th2 cell effector function, and we demonstrate HIF2a to be a central sensor and mediator of this protective axis in vivo.

BIO:

Dr. Oliver (Ollie) Harrison conducted his graduate studies in Immunology at the University of Oxford, investigating how IL-1 family cytokines contribute to CD4+ T cell function during intestinal inflammation, and subsequently, pursued his post-doctoral training at the National Institutes of Health, investigating the induction and regulation of commensal-specific T cells within the skin, and their contribution to wound repair. As a faculty member at Benaroya Research Institute since 2019, his group has investigated the induction of commensal and pathogen-specific T and B cell responses in barrier tissues, seeking to understand how these responses promote tissue physiology and homeostasis.

WEBSITE:

https://www.harrison-lab.org/