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Critical Role for the Chemokine Receptor CXCR6 in Homeostasis and Activation of CD1d-Restricted NKT Cells¹

Elitza Germanov^2,*, Linnea Veinotte^2,*, Robyn Cullen, Erin Chamberlain^*, Eugene C. Butcher and Brent Johnston^3,*,,

^* Department of Microbiology and Immunology, Department of Pathology, and Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada; and Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305; and the Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304

NK T (NKT) cells play important roles in the regulation of diverse immune responses. However, little is known about the mechanisms that regulate homeostasis and activation of these cells. Thymic NKT cells up-regulated the chemokine receptor CXCR6 following positive selection and migrated toward CXCL16 in vitro. However, CXCR6 was not essential for thymic development or maturation. In contrast, liver and lung NKT cells were depleted in CXCR6^+/– and CXCR6^–/– mice. The reduction in liver and lung NKT cells coincided with an increase in bone marrow NKT cells, suggesting a redistribution of NKT cells in CXCR6^–/– animals. In wild-type mice, CXCL16 neutralization reduced accumulation of mature NK1.1⁺, but not immature NK1.1^– NKT cell recent thymic emigrants in the liver. Given that thymic NKT cells are preferentially exported as NK1.1^– cells, this suggests an additional role for CXCR6/CXCL16 in maturation or survival of immature liver NKT cells. CXCL16 blockade did not deplete resident NK1.1⁺ NKT cells, indicating that CXCR6/CXCL16 are not required to retain mature NKT cells in the liver. Cytokine production by liver and spleen NKT cells was impaired in CXCR6^–/– mice following in vivo stimulation with -galactosylceramide, implicating a novel role for CXCR6 in NKT cell activation. Reduced IFN- production was not due to an intrinsic defect as production was normal following PMA and ionomycin stimulation. Preformed transcripts for IL-4, but not IFN-, were reduced in CXCR6^–/– liver NKT cells. These data identify critical roles for CXCR6/CXCL16 in NKT cell activation and the regulation of NKT cell homeostasis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the Terry Fox Foundation awarded to B.J. by the National Cancer Institute of Canada. B.J. holds the Canada Research Chair in Inflammation and Immunity. L.V. is the recipient of a fellowship from the Killam Trusts. E.G. is the recipient of a studentship from the Nova Scotia Health Research Foundation. R.C. is the recipient of a Cancer Research Training Program Award with funding from the Dalhousie Cancer Research Program.

² E.G. and L.V. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Brent Johnston, Department of Microbiology and Immunology, Dalhousie University, Sir Charles Tupper Medical Building, Room 7C, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5. E-mail address: Brent.Johnston{at}Dal.Ca

⁴ Abbreviations used in this paper: NKT cell, NK T cell; -GalCer, -galactosylceramide; DC, dendritic cell; DN, double-negative; DP, double-positive; eGFP, enhanced GFP; FSC, forward light scatter.