MechanoROS-T: Exploring mechanoregulated hydrogen peroxide as a mechanism of T cell activation

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T cells mediate immune responses against infection. They scan our tissues for foreign antigens that that are recognised by cell surfaceT cell receptors (TCRs). Antigen-TCR binding initiates signalling cascades to promote effector functions including cytokine release,proliferation and cytotoxicity. Insights into T cell signalling are key to optimising T cell-based therapies in cancer. Despite itsimportance, how antigen-TCR binding initiates signalling inside the cell is an important unresolved question.Recent structural studies suggest the TCR is rigid and signals without conformational changes, a common cell surface receptoractivation paradigm. Prevailing models in the field draw on the role of receptor tyrosine phosphatases, such as CD45, and TCRmechanosensing properties. Neither fully explains TCR triggering. The immune system exploits reactive oxygen species such ashydrogen peroxide for pathogen killing and as a signalling second messenger - a chemical that modifies proteins and changes theirfunction. Our preliminary data reveals an important new function for hydrogen peroxide in regulating phosphatase-proteininteractions. Here, I propose two new concepts in TCR signalling: 1. Antigen-TCR binding mediates the mechanoregulation of secondmessenger hydrogen peroxide; and 2. Control of target protein phosphorylation and localisation by phosphatases is redox-regulated.My team will use three new mouse models developed in my lab to investigate these concepts. The first enables high-resolutionimaging of hydrogen peroxide spatiotemporal dynamics in primary T cells. The second will facilitate identification of CD45 proximalproteins in primary cells. Finally, a CD45 mutant with impaired redox sensing will allow us to assess its impact on T cell effectorfunctions in vivo. This work will not only deliver fundamental insights into T cell signalling, but also has transformative potential forbroader areas of cell-cell communication, and optimisation of T cell based immunotherapies.