The atypical chemokine receptor CCX-CKR scavenges homeostatic chemokines in circulation and tissues and suppresses Th17 responses.
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.
Comerford
Iain
I
School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia.
Nibbs
Robert J B
RJ
Litchfield
Wendel
W
Bunting
Mark
M
Harata-Lee
Yuka
Y
Haylock-Jacobs
Sarah
S
Forrow
Steve
S
Korner
Heinrich
H
McColl
Shaun R
SR
D000818:Animals; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology; D054415:Chemokine CCL19 / Q000097:blood*; D054421:Chemokine CCL21 / Q000097:blood*; D045142:Cross-Priming / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000097:blood / Q000276:immunology / Q000473:pathology; D006706:Homeostasis / Q000276:immunology*; D053759:Interleukin-23 / Q000378:metabolism; D007700:Kinetics; D008198:Lymph Nodes / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D009928:Organ Specificity; D019707:Receptors, Chemokine / Q000172:deficiency / Q000378:metabolism*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*
D054415:Chemokine CCL19; D054421:Chemokine CCL21; D053759:Interleukin-23; D019707:Receptors, Chemokine