Berg L, Rönnelid J, Klareskog L, Bucht A
Department of Medicine, Unit of Rheumatology, Karolinska Institute, Stockholm, Sweden.
Clin Exp Immunol. 2000 Apr;120(1):174-82. doi: 10.1046/j.1365-2249.2000.01180.x.
T cells implicated in chronic inflammatory diseases such as RA respond weakly when stimulated in vitro with mitogen or antigen. The mechanism behind this hyporesponsiveness is unclear, but a depressed expression of the T cell receptor (TCR)-associated CD3zeta chain has been suggested. In the present work we describe a low expression of CD3zeta in synovial fluid (SF) T cells from RA patients compared with peripheral blood (PB) T cells, but no difference in CD3zeta expression between RA and healthy control PB T cells. In vitro studies demonstrated that granulocytes but not SF macrophages are able to down-regulate the expression of CD3zeta. Through stimulation with anti-CD3 antibodies we demonstrated that the TCR-dependent proliferative response was decreased in SF T cells compared with PB T cells. Stimulation with phorbol ester and ionomycin also resulted in a low proliferative response of SF T cells, indicating that both signal transduction through the TCR (stimulation with anti-CD3) and events further downstream in the signalling pathways (stimulation with phorbol ester and ionomycin) are affected. A similar depression of T cell activity was observed when induction of IL-2 and IL-4 was measured. However, SF T cells were not defective in the induction of interferon-gamma (IFN-gamma) when stimulated with phorbol myristate acetate (PMA)/ionomycin, in contrast to the diminished IFN-gamma response observed after stimulation with anti-CD3. This indicates that the hyporesponsiveness of SF T cells can not be generalized to all T cell functions. The differential response to external stimuli is likely to be of importance for the capacity of SF T cells to influence inflammatory reactions.
参与类风湿关节炎等慢性炎症性疾病的T细胞，在体外受到丝裂原或抗原刺激时反应较弱。这种低反应性背后的机制尚不清楚，但有人提出与T细胞受体（TCR）相关的CD3ζ链表达降低。在本研究中，我们发现类风湿关节炎患者滑液（SF）T细胞中CD3ζ的表达低于外周血（PB）T细胞，但类风湿关节炎患者与健康对照者的PB T细胞之间CD3ζ表达没有差异。体外研究表明，粒细胞而非SF巨噬细胞能够下调CD3ζ的表达。通过抗CD3抗体刺激，我们发现与PB T细胞相比，SF T细胞中TCR依赖性增殖反应降低。佛波酯和离子霉素刺激也导致SF T细胞增殖反应较低，这表明通过TCR的信号转导（抗CD3刺激）和信号通路中下游事件（佛波酯和离子霉素刺激）均受到影响。在检测白细胞介素-2和白细胞介素-4的诱导情况时，观察到了类似的T细胞活性降低。然而，与抗CD3刺激后观察到的干扰素-γ（IFN-γ）反应减弱相反，用佛波醇肉豆蔻酸酯乙酸酯（PMA）/离子霉素刺激时，SF T细胞在诱导IFN-γ方面没有缺陷。这表明SF T细胞的低反应性不能一概而论地应用于所有T细胞功能。对外部刺激的不同反应可能对SF T细胞影响炎症反应的能力很重要。
