The purpose of the project is to investigate the biological roles of members of the chemokine family of cytokines by studying the actions of chemokines and their receptors in vivo, particularly in mouse models of infectious disease and inflammation. Chemokines and their receptors are critical for leukocyte trafficking. Our experiments will provide important information for understanding in which therapeutic contexts in humans manipulating the chemokine system might be beneficial. This laboratory discovered two mouse chemokines, Crg-2/IP-10 and Mig. We discovered human CCR6, the receptor for the chemokine MIP-3alpha, and we have cloned the mouse analogue. In the past year, we cloned and characterized the human CCR9A and CCR9B, receptors for the chemokine TECK. Based on expression and functional data to date, we hypothesize that Crg-2/IP-10 and Mig are important for recruiting T cells and NK cells to sites of inflammation/infection and perhaps for T cell: B cell cooperation; that CCR6 and MIP-3alpha are important for recall responses and antibody production in the mucosa; and that CCR9A and CCR9B are important for thymocyte differentiation and for localization of T cells within the intestine. Part of this project is focused on using gene-targeted mice to inactivate Mig, CCR6, and CCR9, together with anti-chemokine antibodies, to investigate the roles of these ligand/receptor groups in models of immunity and inflammation in mice. Work in the last year has suggested that Mig is important in mice for antibody responses against the bacteria Francisella tularensis and for the modulation of autoimmune encephalomylitis, that Crg-2/IP-10 may play a role in reparative responses to liver injury, and that both Mig and Crg-2/IP-10 are important for adequate host defense against the protozoan parasite Trypanosoma cruzi. In the last year, mice with targeted disruption of the CCR6 and the CCR9 genes have been produced, the latter in collaboration with the Laboratory of Mammalian Genes and Development, NICHD, and preliminary analysis of these mice is underway. Recent work has also extensively characterized the expression of chemokines in Th2-biased and Th1-biased responses to the trematode Schistosoma mansoni in mice,and has suggested that manipulating chemokine activities might affect end-organ inflammation even where patterns of T cell differentiation are unaltered.
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