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 manipulating the chemokine system could be used to treat diseases in which leukocytes play a critical role. In addition, some chemokine receptors are expressed by cancer cells, and these receptors can potentially be exploited for diagnosis and as targets for therapy. In FY 2018 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 characterized subsets of T cells, such as mucosal-associated invariant T (MAIT) cells, that are particularly efficient at migrating across the endothelium, and we have identified some of the molecular features of the surfaces of these cells, including the combination of the chemokine receptors CCR6, CCR5, and CCR2, that make them so efficient. We have continued work on the transcription factor, C/EBPdelta, that regulates a number of genes that encode proteins, such as glycosyltransferases, that are important for the ability of these cells to migrate across endothelium into inflammatory sites. Most recently, we have begun to extend our studies to subsets of human CD4+ (helper) T cells, and we have found that some of the chemokine receptors that are critical for transendothelial migration are shared between MAIT cells and subsets of CD4+ T cells. We are using genome-wide analysis of chromatin and comprehensive analysis of the cells transcriptomes in order to identify 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. We found that one way in that CCR6 contributes to disease is through the recruitment of monocytes that give rise to monocyte-derived dendritic cells that are important for IL-23-induced dermatitis. 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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