Gamma/delta T cells are the predominant source of interleukin-17 in affected joints in collagen-induced arthritis, but not in rheumatoid arthritis.
OBJECTIVE
Although interleukin-17 (IL-17)-producing gamma/delta T cells were reported to play pathogenic roles in collagen-induced arthritis (CIA), their characteristics remain unknown. The aim of this study was to clarify whether gamma/delta T cells or CD4+ T cells are the predominant IL-17-producing cells, and to determine what stimulates gamma/delta T cells to secret IL-17 in mice with CIA. The involvement of IL-17-producing gamma/delta T cells in SKG mice with autoimmune arthritis and patients with rheumatoid arthritis (RA) was also investigated.


METHODS
IL-17-producing cells in the affected joints of mice with CIA were counted by intracellular cytokine staining during 6 distinct disease phases, and these cells were stimulated with various combinations of cytokines or specific antigens to determine the signaling requirements. Similar studies were performed using SKG mice with arthritis and patients with RA.


RESULTS
Gamma/delta T cells were the predominant population in IL-17-producing cells in the swollen joints of mice with CIA, and the absolute numbers of these cells increased in parallel with disease activity. IL-17-producing gamma/delta T cells expressed CC chemokine receptor 6, were maintained by IL-23 but not by type II collagen in vitro, and were induced antigen independently in vivo. Furthermore, IL-17 production by gamma/delta T cells was induced by IL-1beta plus IL-23 independently of T cell receptor. In contrast to what was observed in mice with CIA, IL-17-producing gamma/delta T cells were nearly absent in the affected joints of SKG mice and patients with RA, and Th1 cells were predominant in the joints of patients with RA.


CONCLUSIONS
Gamma/delta T cells were antigen independently stimulated by inflammation at affected joints and produced enhanced amounts of IL-17 to exacerbate arthritis in mice with CIA but not in SKG mice with arthritis or patients with RA.
Ito
Yoshinaga
Y
Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Usui
Takashi
T
Kobayashi
Shio
S
Iguchi-Hashimoto
Mikiko
M
Ito
Hiromu
H
Yoshitomi
Hiroyuki
H
Nakamura
Takashi
T
Shimizu
Masakazu
M
Kawabata
Daisuke
D
Yukawa
Naoichiro
N
Hashimoto
Motomu
M
Sakaguchi
Noriko
N
Sakaguchi
Shimon
S
Yoshifuji
Hajime
H
Nojima
Takaki
T
Ohmura
Koichiro
K
Fujii
Takao
T
Mimori
Tsuneyo
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D005260:Female; D006614:Hindlimb; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D015759:Ionomycin / Q000494:pharmacology; D007596:Joints / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008875:Middle Aged; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D020381:Interleukin-17; D016692:Receptors, Antigen, T-Cell, gamma-delta; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate