The purpose of the project is to clone and characterize novel chemokine receptors in activated lymphocytes. Chemokines are members of a family of more than thirty human cytokines whose best described activities are as chemotactic factors for leukocytes and that act through receptors that are members of the G protein coupled receptor superfamily. Chemokines and their receptors are increasingly recognized as important in the trafficking of lymphocytes in immune and inflammatory responses as well as other aspects of lymphocyte physiology. Because lymphocytes are important in responses to infectious agents as well as in autoimmune diseases, inflammatory disorders, and transplant rejection, secreted factors and receptors that effect lymphocyte recruitment to tissue are potential targets for therapeutic interventions. Characterization of chemokine receptors on lymphocytes is of added medical relevance given the recent discoveries that chemokine receptors function as obligate co-receptors for HIV-1 entry, so that understanding these receptors may lead to novel therapies for preventing and treating HIV infection. Work during the last year has focused on the receptor CXCR6 (STRL33), an HIV/SIV co-receptor that was discovered in this laboratory and whose ligand is CXCL16. By altering amino acids in one of the receptor?s intracellular domains (intracellular loop 2), we have found that functional conformations of the receptor depend on co-operative effects of conserved residues within this domain and that mutations in this domain produce receptors whose activity is cell-type dependent, presumably due to selective use of cell-type specific signaling pathways.
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