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 CCR6, the receptor for the chemokine MIP-3alpha/CCL20, and we have cloned the mouse analogue. We also cloned and characterized the human CCR9A and CCR9B, receptors for the chemokine TECK/CCL25. Part of this project is focused on using 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 with targeted deletion of the genes for CXCL9 and for CCR9. For CXCL9 we have demonstrated functional expression of its receptor, CXCR3, on activated B cells and an unexpected role in supporting antibody production against a bacterial pathogen. For CCR9, we have demonstrated a role in supporting thymocyte development and in maintaining gamma/delta T cells in the gut.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Intramural Research (Z01)
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Hedrick, Michael N; Lonsdorf, Anke S; Shirakawa, Aiko-Konno et al. (2009) CCR6 is required for IL-23-induced psoriasis-like inflammation in mice. J Clin Invest 119:2317-29
Cortes, Lizette M; Mattapallil, Mary J; Silver, Phyllis B et al. (2008) Repertoire analysis and new pathogenic epitopes of IRBP in C57BL/6 (H-2b) and B10.RIII (H-2r) mice. Invest Ophthalmol Vis Sci 49:1946-56
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Barlic, Jana; Zhang, Yuan; Foley, John F et al. (2006) Oxidized lipid-driven chemokine receptor switch, CCR2 to CX3CR1, mediates adhesion of human macrophages to coronary artery smooth muscle cells through a peroxisome proliferator-activated receptor gamma-dependent pathway. Circulation 114:807-19
Wuest, Todd; Farber, Joshua; Luster, Andrew et al. (2006) CD4+ T cell migration into the cornea is reduced in CXCL9 deficient but not CXCL10 deficient mice following herpes simplex virus type 1 infection. Cell Immunol 243:83-9
Wald, Ori; Weiss, Ido D; Wald, Hanna et al. (2006) IFN-gamma acts on T cells to induce NK cell mobilization and accumulation in target organs. J Immunol 176:4716-29
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Fulkerson, Patricia C; Zimmermann, Nives; Brandt, Eric B et al. (2004) Negative regulation of eosinophil recruitment to the lung by the chemokine monokine induced by IFN-gamma (Mig, CXCL9). Proc Natl Acad Sci U S A 101:1987-92
Park, Matthew K; Amichay, Doron; Love, Paul et al. (2002) The CXC chemokine murine monokine induced by IFN-gamma (CXC chemokine ligand 9) is made by APCs, targets lymphocytes including activated B cells, and supports antibody responses to a bacterial pathogen in vivo. J Immunol 169:1433-43
Uehara, Shoji; Song, Kaimei; Farber, Joshua M et al. (2002) Characterization of CCR9 expression and CCL25/thymus-expressed chemokine responsiveness during T cell development: CD3(high)CD69+ thymocytes and gammadeltaTCR+ thymocytes preferentially respond to CCL25. J Immunol 168:134-42

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