Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model.
This report shows that interleukin (IL) 17-producing T helper type 17 (Th17) cells predominantly express CC chemokine receptor (CCR) 6 in an animal model of rheumatoid arthritis (RA). Th17 cells induced in vivo in normal mice via homeostatic proliferation similarly express CCR6, whereas those inducible in vitro by transforming growth factor beta and IL-6 additionally need IL-1 and neutralization of interferon (IFN) gamma and IL-4 for CCR6 expression. Forced expression of RORgamma t, a key transcription factor for Th17 cell differentiation, induces not only IL-17 but also CCR6 in naive T cells. Furthermore, Th17 cells produce CCL20, the known ligand for CCR6. Synoviocytes from arthritic joints of mice and humans also produce a large amount of CCL20, with a significant correlation (P = 0.014) between the amounts of IL-17 and CCL20 in RA joints. The CCL20 production by synoviocytes is augmented in vitro by IL-1beta, IL-17, or tumor necrosis factor alpha, and is suppressed by IFN-gamma or IL-4. Administration of blocking anti-CCR6 monoclonal antibody substantially inhibits mouse arthritis. Thus, the joint cytokine milieu formed by T cells and synovial cells controls the production of CCL20 and, consequently, the recruitment of CCR6+ arthritogenic Th17 cells to the inflamed joints. These results indicate that CCR6 expression contributes to Th17 cell function in autoimmune disease, especially in autoimmune arthritis such as RA.
Hirota
Keiji
K
Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
Yoshitomi
Hiroyuki
H
Hashimoto
Motomu
M
Maeda
Shinji
S
Teradaira
Shin
S
Sugimoto
Naoshi
N
Yamaguchi
Tomoyuki
T
Nomura
Takashi
T
Ito
Hiromu
H
Nakamura
Takashi
T
Sakaguchi
Noriko
N
Sakaguchi
Shimon
S
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D054418:Chemokine CCL20 / Q000235:genetics*; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D054399:Receptors, CCR6 / Q000037:antagonists & inhibitors / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014158:Transcription, Genetic
C108355:CCL20 protein, human; C493447:CCL20 protein, mouse; C498126:CCR6 protein, mouse; D054418:Chemokine CCL20; D019402:Macrophage Inflammatory Proteins; D054399:Receptors, CCR6