Inhibition of CCR6 Function Reduces the Severity of Experimental Autoimmune Encephalomyelitis via Effects on the Priming Phase of the Immune Response

Abstract

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.

Essential role for CCR6 in certain inflammatory diseases demonstrated using specific antagonist and knockin mice

“…Previous studies indicated that CCR6/CCL20 interaction was crucial for the development of EAE, since CCR6 -/-mice were resistant to EAE (15) and anti-CCR6 polyclonal antibody treatment prevented the progression of disease (23). Murine EAE was induced by injection of recombinant mouse myelin oligodendrocyte glycoprotein (rmMOG), a model in which antigen-specific B cells contribute to disease pathogenesis (24).…”

CC Chemokine Receptors and Chronic Inflammation—Therapeutic Opportunities and Pharmacological Challenges

“…Further investigation of the role of CCR6 expressing cells in a cigarette smoke-induced lung injury model was reported by Bracke et al (2006), who showed reduced numbers of DCs, activated CD8 1 T cells, and neutrophils in Ccr6-deficient mice leading to decreased emphysema in this model of chronic obstructive pulmonary disease (COPD). Liston et al (2009) examined the role of CCR6-expressing cells in both the induction and effector phase of the EAE model of demyelination and central nervous system (CNS) inflammation. Ccr6 2/2 mice had reduced disease scores compared with wild-type mice following immunization with myelin oligodendrocyte glycoprotein (MOG) peptides (Liston et al, 2009 Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms near the CCR6 gene on chromosome 6q27 as novel risk loci for autoimmune Graves' disease, generalized vitiligo, and RA (Chu et al, 2011;Jin et al, 2010a;Quan et al, 2010;Stahl et al, 2010).…”

“…Liston et al (2009) examined the role of CCR6-expressing cells in both the induction and effector phase of the EAE model of demyelination and central nervous system (CNS) inflammation. Ccr6 2/2 mice had reduced disease scores compared with wild-type mice following immunization with myelin oligodendrocyte glycoprotein (MOG) peptides (Liston et al, 2009 Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms near the CCR6 gene on chromosome 6q27 as novel risk loci for autoimmune Graves' disease, generalized vitiligo, and RA (Chu et al, 2011;Jin et al, 2010a;Quan et al, 2010;Stahl et al, 2010). Of note Kochi et al (2010) identified a dinucleotide polymorphism in the CCR6 gene that was associated with RA susceptibility in two independent cohort studies and was correlated with the level of CCR6 expression and the presence of IL-17 in patient sera.…”

CCR6 Recruits Regulatory T Cells and Th17 Cells to the Kidney in Glomerulonephritis

“…Whereas the initial site-specific entry of Th17 cells via the choroids plexus into the uninflamed CNS was CCR6 dependent, leukocyte infiltration was CCR6 independent at later stages of disease. 30 Furthermore, Liston et al 31 demonstrated that CCR6 drives the priming phase of EAE by mediating the influx of dendritic cells into and the egress of activated lymphocytes from the draining lymph nodes of the CNS. Both of these proposed mechanism for CCR6 function, however, are less important in renal disease.…”