Lymphocyte Exit from Tissues: Control and Significance to Host Defense

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DESCRIPTION (provided by applicant): The candidate is an accomplished veterinarian with extensive research training in effector T cell trafficking. With guidance of the mentor, Eugene Butcher, the candidate will enhance her training in hands-on laboratory techniques as well as managing, communication, presentation and teaching skills. An additional year of training in the mentor's lab will also be used to complete some components of the work on lymphocyte exit from peripheral tissues as well as to set up models key to the independent phase of the award. Lymphocyte migration from the blood into tissues is well characterized and proven to be a crucial component of inflammation. Tissue infiltrates can serve to fight infectious agents in the affected tissue, but can also cause destructive inflammatory diseases such as arthritis. We have recently shown that lymphocyte migration out of peripheral tissues via the afferent lymph is a regulated and active process, and that T cells require expression of CCR7 to do so. Based on preliminary data, we now propose that during inflammation, CCR7-dependent and CCR7-independent tissue exit mechanisms co-exist. We plan to identify and to test promising candidate exit receptors as well as to determine the importance of tissue exit versus retention in the defense against a lethal infection with influenza virus. The long-term goals of the candidate entail the establishment of a research line that addresses the regulation of lymphocytic infiltrates and the consequences for the defense against pathogens and the development of inflammatory diseases. Relevance - Immune cells enter and subsequently leave tissues, a process necessary to find and destroy invading pathogens. Unfortunately, immune cells sometimes accumulate in tissues where they can cause tissue damage, or they leave the tissue without destroying the pathogen. Defining the molecules involved in tissue exit and knowing the importance of tissue exit in the defense against pathogens will reveal new control points in the regulation of tissue inflammation as well as local immunity.