Sperling A I, Linsley P S, Barrett T A, Bluestone J A
Ben May Institute, University of Chicago, IL 60637.
J Immunol. 1993 Dec 1;151(11):6043-50.
The role of costimulation in the activation of TCR-gamma delta cells in normal mice and mice transgenic (tg) for a TCR-gamma delta receptor was investigated. Activation of TCR-gamma delta cells required two signals. One signal was mediated by TCR occupancy, whereas a second signal was provided by accessory cells. The importance of the CD28/B7 interaction in the delivery of the second signal was demonstrated in multiple ways. First, addition of a soluble fusion protein homolog of CD28, CTLA4Ig, significantly inhibited the activation of G8 tg splenic TCR-gamma delta lymphocytes and intestinal epithelial TCR-gamma delta lymphocytes by Ag-bearing lymphocytes during primary stimulation. Similarly, both proliferation and IFN-gamma production were inhibited by addition of CTLA4Ig to secondary antigenic stimulation of G8 tg TCR-gamma delta cells. Second, an Ag-bearing thymoma, EL-4, was only able to stimulate expanded G8 tg TCR-gamma delta cells when the thymoma expressed B7. This stimulation was blocked by both CTLA4Ig and anti-B7 antibody. Third, antibodies to CD28 were able to mimic the costimulatory affect of APC. TCR-gamma delta cells cultured with either Ag-bearing fixed stimulator cells or submitogenic concentrations of immobilized anti-pan TCR-gamma delta mAb proliferated only in the presence of anti-CD28 mAb. Finally, G8 tg cells produced IL-2 only in the presence of APC costimulation or anti-CD28 antibodies, and the addition of exogenous rIL-2 overcame the need for costimulation. Thus, autocrine IL-2 production is one of the major consequences of TCR-gamma delta cell costimulation. Together these data demonstrate that costimulation is necessary for the activation of TCR-gamma delta cells and can occur through CD28 interaction.
研究了共刺激在正常小鼠和转染TCR-γδ受体的转基因（tg）小鼠中TCR-γδ细胞激活过程中的作用。TCR-γδ细胞的激活需要两个信号。一个信号由TCR占据介导，而第二个信号由辅助细胞提供。通过多种方式证明了CD28/B7相互作用在传递第二个信号中的重要性。首先，添加CD28的可溶性融合蛋白同源物CTLA4Ig，在初次刺激期间显著抑制了携带抗原的淋巴细胞对G8 tg脾TCR-γδ淋巴细胞和肠上皮TCR-γδ淋巴细胞的激活。同样，在对G8 tg TCR-γδ细胞进行二次抗原刺激时，添加CTLA4Ig可抑制增殖和IFN-γ的产生。其次，携带抗原的胸腺瘤EL-4只有在胸腺瘤表达B7时才能刺激扩增的G8 tg TCR-γδ细胞。这种刺激被CTLA4Ig和抗B7抗体阻断。第三，抗CD28抗体能够模拟APC的共刺激作用。用携带抗原的固定刺激细胞或亚致有丝分裂浓度的固定抗泛TCR-γδ单克隆抗体培养的TCR-γδ细胞，只有在存在抗CD28单克隆抗体的情况下才会增殖。最后，G8 tg细胞仅在存在APC共刺激或抗CD28抗体的情况下产生IL-2，添加外源性rIL-2可消除对共刺激的需求。因此，自分泌IL-2的产生是TCR-γδ细胞共刺激的主要后果之一。这些数据共同表明，共刺激是TCR-γδ细胞激活所必需的，并且可以通过CD28相互作用发生。
