Novel approaches to determining the function of tissue-specific regulatory T cells

Informations projet

Tissue-Tregs

N° de convention de subvention: 681373

DOI

10.3030/681373

Projet clôturé

Date de signature de la CE 10 Mai 2016

Date de début 1 Juin 2016

Date de fin 30 Novembre 2021

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 1 999 535,00

Contribution de l’UE

€ 1 999 535,00

Coordonné par

THE BABRAHAM INSTITUTE
United Kingdom

Periodic Reporting for period 4 - Tissue-Tregs (Novel approaches to determining the function of tissue-specific regulatory T cells)

Période du rapport: 2020-07-01 au 2021-11-30

Résumé du contexte et des objectifs généraux du projet

Regulatory T cells (Tregs) are formed through the expression of the transcription factor Foxp3 in T cells, resulting in the rewiring of the cell function into an immunosuppressive phenotype. Recently, it has been proposed that Tregs also have additional tissue-specific physiological roles when resident in different tissues. For example, tissue-specific Tregs residing in the muscle and adipose tissue possess immunological and non-immunological functions in these tissues, distinct from the generic Tregs in circulation. Currently, research into tissue-specific functions of Tregs, or any other migratory cell type, is limited by the available research tools. This project generated new synthetic biology tools for enriching tissue-resident cells and then applied these tools to the study of tissue-resident Tregs in the brain, lung, liver, kidney and pancreas, thus creating a comprehensive atlas of tissue-specific functions. We developed a new system for gene delivery of a Treg-specific survival factor in a tissue-specific manner, allowing this directed expansion and functional testing. We found a key role of brain-resident Tregs in preventing and repairing neurological damage. These studies were extended by systematic molecular, cellular and kinetic analysis using existing innovative methods established in the laboratory. Our tissue-specific gene delivery system will have a profound impact on immunology beyond the direct scope of the project, by providing a proof-of-principle approach for study tissue-specific immunology.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

TISSUE-TREG was based on characterising Treg in the tissue, and using novel synthetic biology circuits to expand these populations in different tissues. The project required substantial development of synthetic biology circuits which needed to be designed, tested and validated in vitro and then new mice generated before testing in vivo. The project saw substantial progress in characterising the biology of tissue Tregs across various tissues, in particular the brain. The work has found that tissue Tregs gain their profile and function in situ following several weeks of residency in the tissue, and migrate out of the tissue again after several months. The profile of a tissue Treg appears to be relatively independent of the tissue in which it resides, demonstrating a conserved pan-tissue function. Work on expanding the tissue Treg populations allowed a direct demonstration of the functional role of brain-resident Tregs in preventing and repairing neurological damage. Key outputs from this work include Pasciuto et al Cell, 2020; Roca et al, Nature Communications, 2021 and Yshii et al, Nature Immunology, in press.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The development of a method to expand up tissue Tregs is beyond state of the art. It is the first time that a multi-cellular synthetic circuit has been used in vivo to couple the behaviour of a migratory cell to its anatomical location. The system provides a proof of principle method to assess the cellular function of migratory immune cells in a tissue-specific manner. This system was patented as PCT/GB2020/052148, with ongoing efforts to commercialise the advance.

Description of work