The atypical chemokine receptor CCX-CKR scavenges homeostatic chemokines in circulation and tissues and suppresses Th17 responses

Comerford, I., Nibbs, R. , Litchfield, W., Bunting, M., Harata-Lee, Y., Haylock-Jacobs, S., Forrow, S., Korner, H. and McColl, S.R. (2010) The atypical chemokine receptor CCX-CKR scavenges homeostatic chemokines in circulation and tissues and suppresses Th17 responses. Blood, 116(20), pp. 4130-4140. (doi: 10.1182/blood-2010-01-264390)

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Publisher's URL: http://dx.doi.org/10.1182/blood-2010-01-264390

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<sup>-/-</sup> mice and confirm this scavenger function in vivo. Compared with WT mice, CCX-CKR<sup>-/-</sup> have a 5-fold increase in the level of CCL21 protein in blood, and 2-3-fold increases in CCL19 and CCL21 in peripheral LNs. The effect of this on immunity was investigated following immunization with MOG<sub>35-55</sub> peptide emulsified in CFA. The subsequent characteristic paralysis develops with enhanced kinetics and severity in CCX-CKR<sup>-/-</sup> compared with WT mice. Despite this, antigen-specific immune responses in the draining LN are diminished in CCX-CKR<sup>-/-</sup> mice. Instead, the earlier onset of disease is associated with enhanced T cell priming in the spleen of CCX-CKR<sup>-/-</sup> mice and a skewing of CD4+ T cell responses toward Th17 rather than Th1. This correlates with increased expression of IL-23 in the spleen of CCX-CKR<sup>-/-</sup> mice and increased CCL21 levels in the CNS following immunization. The early onset of disease in CCX-CKR<sup>-/-</sup> 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 <i>in vivo</i>.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nibbs, Professor Rob
Authors: Comerford, I., Nibbs, R., Litchfield, W., Bunting, M., Harata-Lee, Y., Haylock-Jacobs, S., Forrow, S., Korner, H., and McColl, S.R.
Subjects:R Medicine > R Medicine (General)
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Blood
Publisher:American Society of Hematology
ISSN:0006-4971
ISSN (Online):1528-0020
Published Online:18 June 2010

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