Alegre M L, Shiels H, Thompson C B, Gajewski T F
Howard Hughes Medical Institute, University of Chicago, IL 60637, USA.
J Immunol. 1998 Oct 1;161(7):3347-56.
CTLA-4 is expressed on T cells after activation and shares homology with the CD28 costimulatory receptor. In contrast to CD28, CTLA-4 is thought to be a negative regulator of T cell activation. Cross-linking of CTLA-4 during activation of peripheral T cells reduces IL-2 production and arrests T cells in G1. Much less is known about the function of CTLA-4 in differentiated T cells. We have investigated the expression and function of CTLA-4 in established Th1 and Th2 clones and in bulk populations of Th1 and Th2 cells freshly derived in vitro from TCR transgenic splenocytes. We found that CTLA-4 was induced under similar conditions and with similar kinetics following activation of both Th1 and Th2 clones. However, CTLA-4 expression was much higher in Th2 than Th1 clones and lines. This was confirmed by flow cytometry, confocal microscopy, and Northern blot analysis. The ratio of surface to intracellular expression of CTLA-4 and its rate of endocytosis were similar in Th1 and Th2 clones. Inhibition of binding of CTLA-4 to its ligands using soluble anti-CTLA-4 mAb during stimulation with Ag increased the production not only of IL-2 by Th1 clones, but also that of IL-3 and IFN-gamma by Th1 clones and of IL-3, IL-4, IL-5, and IL-10 by Th2 clones. In contrast, when anti-CTLA-4 was coimmobilized with anti-CD3 and anti-CD28 mAbs, a decrease in the production of multiple cytokines was observed. We conclude that CTLA-4 can function to suppress the production of cytokines produced by both Th1 and Th2 cells.
CTLA-4在激活后的T细胞上表达，与CD28共刺激受体具有同源性。与CD28相反，CTLA-4被认为是T细胞激活的负调节因子。在外周T细胞激活过程中CTLA-4的交联会减少IL-2的产生，并使T细胞停滞在G1期。关于CTLA-4在分化T细胞中的功能了解较少。我们研究了CTLA-4在已建立的Th1和Th2克隆以及从TCR转基因脾细胞体外新鲜获得的Th1和Th2细胞群体中的表达和功能。我们发现，Th1和Th2克隆激活后，CTLA-4在相似的条件下以相似的动力学被诱导。然而，CTLA-4在Th2中的表达远高于Th1克隆和细胞系。这通过流式细胞术、共聚焦显微镜和Northern印迹分析得到证实。CTLA-4的表面与细胞内表达比例及其内吞率在Th1和Th2克隆中相似。在用抗原刺激期间，使用可溶性抗CTLA-4单克隆抗体抑制CTLA-4与其配体的结合，不仅增加了Th1克隆产生IL-2的量，还增加了Th1克隆产生IL-3和IFN-γ的量以及Th2克隆产生IL-3、IL-4、IL-5和IL-10的量。相反，当抗CTLA-4与抗CD3和抗CD28单克隆抗体共固定时，观察到多种细胞因子产生减少。我们得出结论，CTLA-4可以发挥作用抑制Th1和Th2细胞产生的细胞因子。
