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 2017, we have 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. 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, but the mechanism has been unclear. We further characterized the origins and types of monocyte/macrophage and dendritic cell subsets that infiltrate the skin and contribute to the psoriasis-like inflammation. We have identified a subset of inflammatory dendritic cells that enter the outer layers of the skin (epidermis), determined that these and other dendritic cells important for the inflammatory response are derived from infiltrating monocytes, and studied how these cells are recruited. We have found that CCR6 supports the recruitment of the monocytes that give rise to monocyte-derived dendritic cells that are important for IL-23-induced dermatitis. We also determined that the initial responding cells are resident gamma/delta T cells that produce IL-17. Most recently, we have focused on the role of the skin microbiota in lymphocyte homeostasis in the dermis and epidermis and the effect of the microbiota on inflammation in psoriasis-like dermatitis induced by the TLR7/8 agonist, imiquimod. We have been characterizing the roles of chemokines and their receptors in microbiota-dependent positioning of lymphocytes in the skin. In the last year 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 CD8alpha+ T 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 chemokine receptors, that make them so efficient. We have continued work on a transcription factor that regulates a number of genes that encode proteins important for the ability of these cells to migrate across endothelium into inflammatory sites. Most recently, we have begun to extend these studies to subsets of human CD4+ (helper) T cells, initially characterizing the relationships among patterns of expression of chemokine receptors, selectin ligands, and transcription factors of interest. We have found that some of the chemokine receptors that are critical for transendothelial migration are shared between subsets of CD8+ and CD4+ T cells. In the last year we have completed a series of studies on the expression of the chemokine receptor CXCR4 on a range of cancers. We found expression of CXCR4 on significant percentages of major types of kidney, lung, and pancreatic adenocarcinomas, and, notably, on metastases of clear cell renal cell carcinoma and squamous cell carcinoma of the lung. We found particularly high expression of CXCR4 on adrenocortical cancer (ACC) metastases. A first-in-human study using 64Cu-plerixafor for PET in an ACC patient prior to resection of metastases showed heterogeneity among metastatic nodules and good correlations among PET SUVs, CXCR4 staining, and CXCR4 mRNA. Additionally, we were able to show that CXCR4 expression correlated with the rates of growth of the pulmonary lesions in this patient.
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