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* School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia, Australia;
Comparative Genomics Centre, School of Pharmacy and Molecular Sciences, James Cook University, Townsville, Queensland, Australia; and
Biomedical Research Center, University of British Columbia, Vancouver, British Columbia, Canada
Chemokines are essential for homeostasis and activation of the immune system. The chemokine ligand/receptor pairing CCL20/CCR6 is interesting because these molecules display characteristics of both homeostatic and activation functions. These dual characteristics suggest a role for CCR6 in the priming and effector phases of the immune response. However, while CCR6 has been implicated in the effector phase in several models, a role in the priming phase is less clear. Herein we analyze the role of CCR6 in these two important arms of the immune response during experimental autoimmune encephalomyelitis (EAE). Both CCR6 and its chemokine ligand CCL20 were up-regulated in the draining lymph nodes and spinal cord during EAE, and CCR6 was up-regulated on CD4+ T cells that had divided following induction of EAE. The functional role of this expression was demonstrated by impaired development of EAE in gene-targeted CCR6-deficient mice and in mice treated either with a neutralizing anti-CCR6 Ab or with a novel receptor antagonist. Inhibition of EAE was due to reduced priming of autoreactive CD4+ T cells probably as a result of impaired late-stage influx of dendritic cells into draining lymph nodes. This was accompanied by reduced egress of activated lymphocytes from the lymph nodes. These results demonstrate a novel role for CCR6 in the mechanism of autoreactive lymphocyte priming and emigration to the efferent lymphatics.
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 the National Health and Medical Research Council of Australia and the Multiple Sclerosis Society.
2 Current address: University of Leuven, Leuven 3000, Belgium, and the Flanders Institute of Biotechnology, Gent 9052, Belgium.
4 Address correspondence and reprint requests to Dr. Shaun R. McColl, School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia 5005, Australia. E-mail address: shaun.mccoll{at}adelaide.edu.au
5 Abbreviations used in this paper: DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; LN, lymph node; MOG, myelin oligodendrocyte glycoprotein; NRIgG, normal rabbit IgG; PLP, proteolipid protein; S1P, sphingosine-1-phosphate.
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