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

Iain Comerford, Robert J B Nibbs, Wendel Litchfield, Mark D Bunting, Yuka Harata-Lee, Sarah Haylock-Jacobs, Steve Forrow, Heinrich Korner, Shaun R McColl

Research output: Contribution to journalArticle

54 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4130-40
Number of pages11
JournalBlood
Volume116
Issue number20
DOIs
Publication statusPublished - 18 Nov 2010
Externally publishedYes

Keywords

  • Animals
  • Central Nervous System/immunology
  • Chemokine CCL19/blood
  • Chemokine CCL21/blood
  • Cross-Priming/immunology
  • Encephalomyelitis, Autoimmune, Experimental/blood
  • Homeostasis/immunology
  • Interleukin-23/metabolism
  • Kinetics
  • Lymph Nodes/immunology
  • Mice
  • Mice, Inbred C57BL
  • Neutralization Tests
  • Organ Specificity
  • Receptors, Chemokine/deficiency
  • Spleen/immunology
  • Th1 Cells/immunology
  • Th17 Cells/immunology

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