The Journal of Experimental Medicine
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Published online November 19, 2007
doi:10.1084/jem.20071397
The Journal of Experimental Medicine, Vol. 204, No. 12, 2803-2812
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Hirota et al.
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BRIEF DEFINITIVE REPORT

 Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model

Keiji Hirota1,2, Hiroyuki Yoshitomi1,3, Motomu Hashimoto1, Shinji Maeda1, Shin Teradaira1, Naoshi Sugimoto1, Tomoyuki Yamaguchi1, Takashi Nomura1, Hiromu Ito3, Takashi Nakamura3, Noriko Sakaguchi1, and Shimon Sakaguchi1,2

1 Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
2 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
3 Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan

CORRESPONDENCE Shimon Sakaguchi: shimon{at}frontier.kyoto-u.ac.jp

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 β and IL-6 additionally need IL-1 and neutralization of interferon (IFN) {gamma} and IL-4 for CCR6 expression. Forced expression of ROR{gamma}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-1β, 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.

K. Hirota and H. Yoshitomi contributed equally to this work.


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