The purposes of the project are to investigate the biological roles of members of the chemokine family of cytokines, to use chemokine receptors to understand the relationships between the trafficking patterns and broader biological functions of subsets of effector/memory T cells, and to understand the contributions of the chemokine system to infectious and inflammatory/autoimmune disease and cancer. Chemokines and their receptors are critical for leukocyte trafficking, and our experiments are directed to understanding how blocking or otherwise manipulating the chemokine system could be used in treating disease. In FY 2019 we have continued studies of the process whereby effector/memory T cells migrate from the blood, across the layer of endothelial cells that line the inside off the blood vessel, into a site of tissue infection or inflammation. We have built on our work with mucosal-associated invariant T (MAIT) cells in order to investigate the mechanisms underlying the ability of human CD4+ T cells that co-express multiple chemokine receptors to extravasate efficiently, and how extravasation and T cell effector function may be coordinately regulated at the level of gene regulation. We are using genome-wide analysis of chromatin and comprehensive analysis of the transcriptomes of both MAIT cells and CD4+ T cells in order to identify shared mechanisms of gene regulation that underlie the ability of the cells to migrate efficiently. In the last year we have also continued to investigate mouse models of skin inflammation that have features of psoriasis. One model involves injection of a cytokine, IL-23, which appears to have a role not only in psoriasis, but also in other immune-mediated diseases, such as Crohns disease. A second model uses topical application of a pharmaceutical cream, Aldara, which contains the TLR7/8 agonist, imiquimod. We and others had described that the chemokine receptor CCR6 is expressed by IL-23-dependent T cells that produce the cytokines IL-17 and IL-22. IL-22 and IL-17 are important in producing disease in the mouse psoriasis model and are thought to be important in causing tissue injury in some autoimmune diseases. We have shown previously that mice lacking CCR6 are resistant to the IL-23-induced disease and show diminished response to Aldara. Most recently, we have focused on the role of the skin microbiota in lymphocyte homeostasis in the epidermis and the effect of the microbiota on the inflammation induced by imiquimod. We have continued to characterize the roles of chemokines and their receptors in microbiota-dependent positioning of lymphocytes in the skin and have begun using two-photon microscopy in order to visualize trafficking of lymphocytes in the skin in vivo.
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