Inhibition of CCR6 function reduces the severity of experimental autoimmune encephalomyelitis via effects on the priming phase of the immune response.
Chemokines are essential for homeostasis and activation of the immune system. The chemokine ligand/receptor pairing CCL20/CCR6 is interesting because these molecules display characteristics of both homeostatic and activation functions. These dual characteristics suggest a role for CCR6 in the priming and effector phases of the immune response. However, while CCR6 has been implicated in the effector phase in several models, a role in the priming phase is less clear. Herein we analyze the role of CCR6 in these two important arms of the immune response during experimental autoimmune encephalomyelitis (EAE). Both CCR6 and its chemokine ligand CCL20 were up-regulated in the draining lymph nodes and spinal cord during EAE, and CCR6 was up-regulated on CD4(+) T cells that had divided following induction of EAE. The functional role of this expression was demonstrated by impaired development of EAE in gene-targeted CCR6-deficient mice and in mice treated either with a neutralizing anti-CCR6 Ab or with a novel receptor antagonist. Inhibition of EAE was due to reduced priming of autoreactive CD4(+) T cells probably as a result of impaired late-stage influx of dendritic cells into draining lymph nodes. This was accompanied by reduced egress of activated lymphocytes from the lymph nodes. These results demonstrate a novel role for CCR6 in the mechanism of autoreactive lymphocyte priming and emigration to the efferent lymphatics.
Liston
Adrian
A
School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia, Australia.
Kohler
Rachel E
RE
Townley
Scott
S
Haylock-Jacobs
Sarah
S
Comerford
Iain
I
Caon
Adriana C
AC
Webster
Julie
J
Harrison
Jodie M
JM
Swann
Jeremy
J
Clark-Lewis
Ian
I
Korner
Heinrich
H
McColl
Shaun R
SR
D000595:Amino Acid Sequence; D000818:Animals; D054418:Chemokine CCL20 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005260:Female; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D042601:Lymphatic Vessels / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D054399:Receptors, CCR6 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology*; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism / Q000473:pathology
C493447:CCL20 protein, mouse; C498126:CCR6 protein, mouse; D054418:Chemokine CCL20; D054399:Receptors, CCR6