1. The atypical chemokine receptor CCX-CKR scavenges homeostatic chemokines in circulation and tissues and suppresses Th17 responses.
- Author
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Comerford I, Nibbs RJ, Litchfield W, Bunting M, Harata-Lee Y, Haylock-Jacobs S, Forrow S, Korner H, and McColl SR
- Subjects
- Animals, Central Nervous System immunology, Central Nervous System pathology, Cross-Priming immunology, Encephalomyelitis, Autoimmune, Experimental blood, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental pathology, Interleukin-23 metabolism, Kinetics, Lymph Nodes pathology, Mice, Mice, Inbred C57BL, Neutralization Tests, Organ Specificity, Receptors, Chemokine deficiency, Spleen immunology, Spleen pathology, Th1 Cells immunology, Chemokine CCL19 blood, Chemokine CCL21 blood, Homeostasis immunology, Lymph Nodes immunology, Receptors, Chemokine metabolism, Th17 Cells immunology
- 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.
- Published
- 2010
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