Control of T cell immunity by the extracellular redox environment of tissues

T cells are critical to host defence but their dysregulated function contributes to cancer, autoimmunity and immunopathology during infection. T cells must integrate cues from diverse tissue environments in which they operate. Emerging evidence shows that reactive oxygen species (ROS) are not merely toxic byproducts of metabolism but second messengers required for T cell activation and differentiation. How the extracellular redox environment guides T cell function within tissues is unclear. We have found that T cells are highly sensitive to their extracellular redox environment, suppressed in tumours by release of extracellular antioxidant proteins that deprive T cells of extracellular ROS required for activation. T cells can both generate and sense extracellular ROS, suggesting that ROS may function not only as instructive tissue cues but as paracrine signals between immune cells within tissues. This research will ask: - How do extracellular redox states regulate T cell behaviour in cancer, autoimmunity and infection? - How do T cells generate and respond to extracellular ROS? - Can the extracellular redox environment be therapeutically targeted? This work will establish the extracellular redox environment of tissues as a fundamental axis of immune regulation and test whether this presents opportunities for therapeutic intervention in infection, autoimmunity and cancer.