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Deciphering the role of HIF-1alpha in tissue resident T cells during health and disease

English title Deciphering the role of HIF-1alpha in tissue resident T cells during health and disease
Applicant King Carolyn
Number 197683
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.10.2020 - 30.09.2024
Approved amount 720'000.00
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Keywords (8)

lung; mucosal immunology; memory; infection; CD4; influenza; resident memory; HIF-1alpha

Lay Summary (German)

Lead
Obwohl sich viele immunologische Studien auf T-Zell-Reaktionen in Blut (im Fall von Humanforschung) oder lymphoiden Organen (im Fall von Tierversuchen) konzentrieren, wird zunehmend klar, dass T-Zell-Reaktionen in Barrieregeweben für den Schutz des Wirts entscheidend sind.
Lay summary
In den letzten 10 Jahren wurde gezeigt, dass T-Zell-Reaktionen in Barrieregeweben wie Lunge, Haut und Darm nicht nur eine wichtige Rolle bei der Beseitigung infektiöser Krankheitserreger spielen, sondern auch bei der Aufrechterhaltung einer gesunden und tolerogenen Umgebung im Steady State. Wir haben kürzlich eine neue Population von T-Zellen identifiziert, die sich nach einer Influenza-Infektion stabil in der Lunge befindet. Diese Population drückt einen Transkriptionsfaktor aus, der für seine Fähigkeit bekannt ist, das Überleben der Zellen unter Umweltstress zu fördern. Das Ziel dieses Vorschlags ist es zu verstehen, wie diese T-Zellen erzeugt werden und welchen Beitrag sie zur Pathologie oder zum Schutz des Wirts nach einer Herausforderung leisten. Wir wollen diese Studien weiter auf neue Krankheitsmodelle wie Asthma und Krebs ausweiten.
Direct link to Lay Summary Last update: 29.09.2020

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Abstract

During the last ten years, a population of clonally expanded T cells that take up permanent residence in barrier tissues has been identified. It is increasingly clear that tissue resident memory (TRM) cells play critical roles not only in clearing infection but also in tissue remodeling, repair and protection against subsequent infection. Importantly, the non-circulating status of TRM cells allows them to rapidly respond at the site of antigen exposure, making them an attractive therapeutic target for various immune interventions. We recently identified a novel population of resident T cells that orchestrates humoral immunity in the lung mucosa. Preliminary experiments presented here suggest that HIF1, a transcription factor renowned for it’s ability to promote glycolysis and cell survival in oxygen/nutrient poor environments, is gradually upregulated by this subset and stably maintained under homeostatic conditions. The goal of this proposal is to understand how HIF1 activity regulates the generation, survival, localization and function of these cells. We hypothesize that HIF1 acts as a checkpoint for T cell diversification during recall and additionally plays a role in mitigating excessive inflammatory responses that if left unchecked, would destroy the memory T cell niche and/or cause damage to the tissue. We further aim to extend our studies into new disease models where understanding the interplay between HIF1+ and HIF1- TRM cell subsets may have implications for reinvigorating or suppressing T cell responses in tissues and tumors. We have 4 specific aims: Aim 1: Define the signals that induce the generation and maintenance of HIF1+ TRH cells in the lungAim 2: Characterize the spatial localization and immune cell interactions of HIF1+ and HIF1- TRH cells Aim 3: Investigate the impact of HIF1 deletion or stabilization on tissue homeostasis and immunityAim 4: Explore the role of T cell intrinsic HIF expression in antibody mediated allergic disease and cancer
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