Maurice M M, van der Voort E A, Leow A, Levarht N, Breedveld F C, Verweij C L
Department of Rheumatology, Leiden University Medical Center, The Netherlands.
Eur J Immunol. 1998 May;28(5):1554-62. doi: 10.1002/(SICI)1521-4141(199805)28:05<1554::AID-IMMU1554>3.0.CO;2-N.
In rheumatoid arthritis (RA), T cells in the inflamed joint are considered to play a crucial role in the pathogenesis. However, despite the fact that synovial T cells have an activated memory phenotype, they are functionally suppressed upon combined CD3 and CD28 stimulation. Here, we analyzed the contribution of both CD3 and CD28 to the hyporesponsiveness of synovial T cells in RA. In contrast to the low CD3 responsiveness of synovial fluid (SF) T cells compared to peripheral blood (PB) T cells, the CD28 co-stimulatory response was observed to be unaffected. Hyporesponsiveness of SF T cells has previously been associated with decreased levels of intracellular glutathione (GSH), an antioxidant and regulator of the intracellular redox state. Treatment of SF T cells with N-acetylcysteine, an antioxidant and replenisher of GSH, selectively improved CD3-induced responses, while leaving CD28 responsiveness unaffected. These data show that the CD3 pathway is highly sensitive to intracellular GSH alterations, whereas CD28 responsiveness is relatively refractory. Furthermore, in support for a functional role of CD28 co-stimulation, it was demonstrated that CD28 ligation acted in synergy with the IL-2 receptor gamma chain signaling cytokine IL-15 in the enhancement of the ex vivo survival of SF T cells. These data indicate that CD28 co-stimulatory capacity of SF T cells, in contrast to CD3 stimulation, remains intact despite an altered intracellular redox state. Thereby, CD28 stimulation may contribute to the persistence of T cells at the site of inflammation, which might be of relevance in the pathogenesis of RA.
在类风湿性关节炎（RA）中，炎症关节中的T细胞被认为在发病机制中起关键作用。然而，尽管滑膜T细胞具有活化的记忆表型，但在CD3和CD28联合刺激下它们在功能上受到抑制。在此，我们分析了CD3和CD28对RA中滑膜T细胞低反应性的作用。与外周血（PB）T细胞相比，滑液（SF）T细胞的CD3反应性较低，而CD28共刺激反应未受影响。SF T细胞的低反应性先前已与细胞内谷胱甘肽（GSH）水平降低相关，GSH是一种抗氧化剂和细胞内氧化还原状态的调节剂。用N - 乙酰半胱氨酸（一种GSH的抗氧化剂和补充剂）处理SF T细胞，选择性地改善了CD3诱导的反应，而CD28反应性未受影响。这些数据表明CD3途径对细胞内GSH改变高度敏感，而CD28反应性相对难以改变。此外，为了支持CD28共刺激的功能作用，已证明CD28连接与IL - 2受体γ链信号细胞因子IL - 15协同作用，增强了SF T细胞的体外存活。这些数据表明，与CD3刺激相比，尽管细胞内氧化还原状态发生改变，SF T细胞的CD28共刺激能力仍保持完整。因此，CD28刺激可能有助于T细胞在炎症部位的持续存在，这可能与RA的发病机制有关。
