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/CXCL10 and Mig/CXCL9 that are highly induced by gamma interferon. We discovered human - and cloned the mouse analogue of - CCR6, the receptor for the chemokine MIP-3alpha/CCL20 and reportedly for the beta-defensin anti-microbial peptides. We also cloned and characterized the human CCR9A and CCR9B, receptors for the chemokine TECK/CCL25. Part of this project uses gene-targeted mice to investigate the roles of these ligand/receptor groups in models of immunity and inflammation in mice. Work in the last year has focused on the analysis of mice that we derived with targeted deletion (knockout/green fluorescent protein knock-in) of the gene for CCR6. CCR6 has been reported to serve as an important chemokine receptor on dendritic cells, which are the critical cells for processing antigens, activating lymphocytes and initiating immune responses. Nonetheless, in collaborative recent work with our CCR6 knockout mice, CCR6 has been found not to be necessary for two relevant aspects of dendritic cell biology: maturation mediated by beta-defensins and positioning of a unique CD11b+ subset found under the epithelial dome of Peyer s patches.
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