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|Title:||The atypical chemokine receptor CCX-CKR scavenges homeostatic chemokines in circulation and tissues and suppresses Th17 responses|
|Citation:||Blood, 2010; 116(20):4130-4140|
|Publisher:||Amer Soc Hematology|
|Iain Comerford, Robert J. B. Nibbs, Wendel Litchfield, Mark Bunting, Yuka Harata-Lee, Sarah Haylock-Jacobs, Steve Forrow, Heinrich Korner and Shaun R. McColl|
|Abstract:||Our previous in vitro studies led to proposals that the atypical chemokine receptor CCX-CKR is a scavenger of CCR7 ligand homeostatic chemokines. In the present study, we generated CCX-CKR(-/-) mice and confirm this scavenger function in vivo. Compared with wild-type mice, CCX-CKR(-/-) have a 5-fold increase in the level of CCL21 protein in blood, and 2- to 3-fold increases in CCL19 and CCL21 in peripheral lymph nodes. The effect of these protein increases on immunity was investigated after immunization with MOG(35-55) peptide emulsified in complete Freund adjuvant (CFA). The subsequent characteristic paralysis develops with enhanced kinetics and severity in CCX-CKR(-/-) versus wild-type mice. Despite this effect, antigen-specific immune responses in the draining lymph nodes are diminished in CCX-CKR(-/-) mice. Instead, the earlier onset of disease is associated with enhanced T-cell priming in the CCX-CKR(-/-) spleen and a skewing of CD4(+) T-cell responses toward Th17 rather than Th1. This observation correlates with increased expression of IL-23 in the CCX-CKR(-/-) spleen and increased CCL21 levels in the central nervous system postimmunization. The early onset of disease in CCX-CKR(-/-) mice is reversed by systemic administration of neutralizing anti-CCL21 antibodies. Thus, by regulating homeostatic chemokine bioavailability, CCX-CKR influences the localization, kinetics, and nature of adaptive immune responses in vivo.|
|Keywords:||Central Nervous System|
Mice, Inbred C57BL
Encephalomyelitis, Autoimmune, Experimental
|Rights:||Copyright 2010 by The American Society of Hematology; all rights reserved.|
|Appears in Collections:||Aurora harvest 5|
Molecular and Biomedical Science publications
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