Inflammation-driven T Cell Responses and their Dichotomous Effect on Host Immunity

Project Summary Memory CD8 T cells can be reactivated by a T cell receptor (TCR) signal, but also pro-inflammatory cytokines. Reactivation in the absence of a TCR signal is referred to as bystander-activation and has been observed across a wide range of different inflammatory processes, including infections, autoimmunity and cancer. Bystander activated T cell exert effector function and secrete effector molecules such as granzyme B and interferon gamma, which contribute to enhancing host immunity, but also exacerbate tissue damage and prevent resolution of inflammation. The pro-inflammatory signals that elicit bystander activation have been fairly well defined, but little is known regarding the regulatory signals that can inhibit or turn off effector function by bystander activated memory CD8 T cells. In contrast, the mechanisms that negatively regulate effector function of memory CD8 T cells that are reactivated in a TCR-dependent manner are well established. Our preliminary data suggest that there are distinct regulatory mechanisms in place for memory CD8 T cells reactivated by TCR- vs. cytokine-mediated signals. We specifically propose to study these mechanisms in the context of tissue-based immune responses to determine how a perturbation of these regulatory systems affects pathogen clearance, as well as tissue damage and re-establishing of tissue homeostasis. Ultimately, our goal is to use the gained insights to develop strategies that will allow for therapeutic targeting of T cell- mediated tissue damage.