Identifying the requirements for T cell exit from peripheral tissues during an immune response

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Project Summary An effective immune response requires moving the right cells to the right place at the right time. T cells, an important set of immune cells, migrate extensively to fight infection. At steady state, T cells circulate among specialized organs called lymph nodes, which are found throughout the body. Pathogens and debris drain from infected tissues to local lymph nodes, and T cells survey the lymph nodes for signs of infection. After activation and proliferation in the lymph node, T cells go to the site of infection. There, they fight infection and may ultimately die, stay and form long-lived “resident memory” cells, or leave into lymphatics and recirculate. It has been shown that the chemokine receptor CCR7 brings T cells into the lymph node, while sphingosine 1-phosphate receptor 1 (S1PR1) allows them to leave. Recent studies have provided an increasingly good understanding of T cell entry into infected tissues, but exit from these tissues is still very poorly understood. The cues that guide T cell exit from inflamed tissues are important to elucidate, as they likely regulate the duration of inflammation and what kind of immune memory is generated. The goals of my work are to identify requirements for T cell exit from infected tissues, which will ultimately enable a better understanding of how T cell exit from tissues affects the immune response. In my first aim, I will assess the types of cells exiting and the role of CCR7 and S1P receptors in T cell exit from inflamed skin, and in my second aim I will assess the role of the S1P transporter SPNS2 in generating the S1P gradients that guide T cell egress from skin. My results may provide insight into strategies to limit chronic inflammation, as well as strategies to develop vaccines that generate protective resident memory T cells.