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Cutting Edge: The Silent Chemokine Receptor D6 Is Required for Generating T Cell Responses That Mediate Experimental Autoimmune Encephalomyelitis¹

LiPing Liu^*, Gerard J. Graham, Anita Damodaran^*,, Taofang Hu^*, Sergio A. Lira, Margaret Sasse^*, Claudia Canasto-Chibuque, Donald N. Cook^¶ and Richard M. Ransohoff^2,*

^* Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, United Kingdom; University of Southern California, Los Angeles, CA 90089; Immunobiology Center, Mount Sinai School of Medicine, New York, NY 10029; and ^¶ National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709

D6, a promiscuous nonsignaling chemokine binding molecule expressed on the lymphatic endothelium, internalizes and degrades CC chemokines, and D6^–/– mice demonstrated increased cutaneous inflammation following topical phorbol ester or CFA injection. We report that D6^–/– mice were unexpectedly resistant to the induction of experimental autoimmune encephalomyelitis due to impaired encephalitogenic responses. Following induction with myelin oligodendroglial glycoprotein (MOG) peptide 35–55 in CFA, D6^–/– mice showed reduced spinal cord inflammation and demyelination with lower incidence and severity of experimental autoimmune encephalomyelitis attacks as compared with D6^+/+ littermates. In adoptive transfer studies, MOG-primed D6^+/– T cells equally mediated disease in D6^+/+ or D6^–/– mice, whereas cells from D6^–/– mice transferred disease poorly to D6^+/– recipients. Lymph node cells from MOG-primed D6^–/– mice showed weak proliferative responses and made reduced IFN- but normal IL-5. CD11c⁺ dendritic cells accumulated abnormally in cutaneous immunization sites of D6^–/– mice. Surprisingly, D6, a "silent" chemokine receptor, supports immune response generation.

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