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

journal contribution
posted on 2023-05-17, 05:05 authored by Comerford, I, Nibbs, RJB, Litchfield, W, Bunting, M, Harata-Lee, Y, Haylock-Jacobs, S, Forrow, S, Heinrich KornerHeinrich Korner, McColl, SR
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 MOG35-55 peptide emulsified in complete Freund adjuvant (CFA). The subsequent characteristic paralysis develops with enhanced kinetics and severity in CCXCKR -/- 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 CCXCKR -/- 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 CCXCKR -/- 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.


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Menzies Institute for Medical Research


Amer Soc Hematology

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Copyright ©2010 American Society of Hematology

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