Effector function of type II collagen-stimulated T cells from rheumatoid arthritis patients: cross-talk between T cells and synovial fibroblasts.
OBJECTIVE
To investigate the effector function exerted by type II collagen (CII)-stimulated T cells on rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS), and to determine their contribution to RA pathogenesis.


METHODS
We used enzyme-linked immunosorbent assays to measure the levels of interleukin-15 (IL-15), tumor necrosis factor alpha (TNFalpha), and IL-18 production by FLS that were cocultured with antigen-activated T cells. Likewise, we analyzed the levels of interferon-gamma (IFN gamma) and IL-17 production by RA T cells coincubated with FLS. To investigate the cross-talk between CII-stimulated T cells and RA FLS, we examined the effect of using a transwell membrane to separate T cells and FLS in a culture chamber, as well as the effect of adding an antibody to block CD40 ligation.


RESULTS
The levels of IL-15, TNF alpha, IFN gamma, and IL-17 were all significantly increased in the serum of RA patients compared with normal control serum. Among the patients, the group with a stronger T cell proliferation response to CII showed higher levels of these inflammatory mediators. When coincubated with RA FLS, these T cells induced the production of IL-15, TNF alpha, and IL-18 by FLS with an intensity that increased in proportion to the duration of CII stimulation. T cells, in turn, responded to FLS stimulation by secreting higher amounts of IL-17 and IFN gamma in coculture. Interestingly, T cells that were activated by CII for longer periods of time showed stronger induction of these cytokines. The cross-talk between T cells and FLS appeared to require direct cell-cell contact as well as CD40 ligation, at least in part.


CONCLUSIONS
Through repeated stimulation by CII, RA synovial T cells became trained effector cells that induced the production of proinflammatory mediators by FLS, while in the process the T cells becoming more sensitized to the activation signal from FLS.
Cho
Mi-La
ML
Catholic Research Institutes of Medical Sciences, The Catholic University of Korea, Seoul, South Korea.
Yoon
Chong-Hyeon
CH
Hwang
Sue-Yun
SY
Park
Mi-Kyung
MK
Min
So-Youn
SY
Lee
Sang-Heon
SH
Park
Sung-Hwan
SH
Kim
Ho-Youn
HY
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000503:physiopathology*; D019013:CD40 Antigens / Q000378:metabolism; D002450:Cell Communication; D002455:Cell Division; D002460:Cell Line; D018920:Coculture Techniques; D024043:Collagen Type II / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007378:Interleukins / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D019013:CD40 Antigens; D024043:Collagen Type II; D016207:Cytokines; D018836:Inflammation Mediators; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha