T cells use hydrogen peroxide as a chemical messenger to switch on their attack against infections, and a new set of mouse models will reveal exactly how that happens. The problem is that scientists do not understand the very first step of T cell activation—how binding a foreign fragment to the receptor on the cell surface triggers signals inside the cell. Existing explanations, based on phosphatase enzymes or mechanical force, do not fully account for what happens. This project proposes that the mechanical force of antigen binding generates a burst of hydrogen peroxide, which then alters nearby proteins and allows signalling to begin. If the research succeeds, it will fill a fundamental gap in immunology. The immediate impact is conceptual: a new mechanism for how cells sense and respond to their environment. In the longer term, understanding this redox-controlled switch could help engineers design better T cell-based cancer immunotherapies, for example by making engineered T cells more reliably responsive to tumours. The work is primarily curiosity-driven fundamental science, but similar discoveries about signalling molecules have previously opened entirely new drug development pathways.
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T cells mediate immune responses against infection. They scan our tissues for foreign antigens that that are recognised by cell surface T 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 its importance, 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 receptor activation paradigm. Prevailing models in the field draw on the role of receptor tyrosine phosphatases, such as CD45, and TCR mechanosensing properties. Neither fully explains TCR triggering. The immune system exploits reactive oxygen species such as hydrogen peroxide for pathogen killing and as a signalling second messenger - a chemical that modifies proteins and changes their function. Our preliminary data reveals an important new function for hydrogen peroxide in regulating phosphatase-protein interactions. Here, I propose two new concepts in TCR signalling: 1. Antigen-TCR binding mediates the mechanoregulation of second messenger 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-resolution imaging of hydrogen peroxide spatiotemporal dynamics in primary T cells. The second will facilitate identification of CD45 proximal proteins in primary cells. Finally, a CD45 mutant with impaired redox sensing will allow us to assess its impact on T cell effector functions in vivo. This work will not only deliver fundamental insights into T cell signalling, but also has transformative potential for broader areas of cell-cell communication, and optimisation of T cell based immunotherapies.
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