Report
Teaser, summary, work performed and final results
Periodic Reporting for period 2 - Tissue-Tregs (Novel approaches to determining the function of tissue-specific regulatory T cells)
Teaser
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...
Summary
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. A vital part of immunological studies is cell depletion, yet a major limitation of all available methods is that they deplete target cells across the entire organism. This makes it extremely difficult to ascertain the function of tissue-resident Tregs, as systemic deletion results in severe autoimmunity, confounding the study of tissue-specific subsets. In order to assess these tissue-resident subsets new research tools are required to deplete the target cells in a specific anatomical region while leaving the same cell type unaffected in other organs. This project proposes to generate new synthetic biology tools for depleting tissue-resident cells and then to apply 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. These studies will be extended by systematic molecular, cellular and kinetic analysis using existing innovative methods established in the laboratory. Finally, our tissue-specific deletion system will have a profound impact on immunology beyond the direct scope of the project, as the tools will be developed to allow flexible application to any cell type. In essence, this is a field of research currently held back by the absence of appropriate tools, waiting for the generation of a new toolkit.
Work performed
TISSUE-TREG is based on characterising Treg in the tissue, and using novel synthetic biology circuits to either deplete or expand these populations in different tissues. The project requires substantial development of synthetic biology circuits which need to be designed, tested and validated in vitro and then new mice generated before testing in vivo. The project has seen substantial progress in characterising the biology of tissue Tregs across various tissues (Research Track 2). In summary, 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 has proceeded, with new synthetic biology circuits that are able to expand up tissue Tregs just in a single organ, for example the brain. Functional outcomes are ongoing.
Final results
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. In the second half of the project it is expected to complete the reverse circuit, one of tissue-specific depletion.