Metabolite- and cytokine-mediated signals interact to control human CD8 T cell responses in tissues - Project Summary Inhibitory mechanisms and negative feedback loops are in place soon after a T cell is successfully activated to temporally limit and restrain effector function, which is critical to prevent excessive tissue destruction. Some inhibitory signals are CD8 T cell intrinsic and others are provided by professional antigen-presenting cells (APCs), regulatory T cells (Tregs), cytokines and metabolites. Most studies examining the regulation of T cell responses in tissues have been performed in the mouse model system, while the nature of activating and inhibitory signals for T cells in human tissues is still poorly defined. T cells in human tissues, particularly human barrier tissues, appear to be continuously exposed to an array of activating and inhibitory signals. We report here that pro- and anti-inflammatory signals are present in healthy, sterile human tissue. We propose to test the hypothesis that activating and inhibitory signals in the form of cytokines and metabolites are present even in healthy, sterile human tissue to regulate effector function of CD8 T cells located in the tissue. Importantly, based on our preliminary data we propose that the tissue itself provides at least some of the pro-inflammatory signals at steady state suggesting that even healthy tissues can direct T cell responses. Defining which immunomodulatory signals are present in healthy as well as acutely infected human tissues is relevant to better understand how immune quiescence is achieved while also maintaining immune responsiveness and function. We established a human cohort that will allow us to define how the balance of activating and inhibitory signals signals is altered during an acute tissue infection. Ultimately, this may reveal new strategies to specifically curtail unwanted T cell activation and return to a state of tissue homeostasis.
