Böhmig G A, Kovarik J, Holter W, Pohanka E, Zlabinger G J
Institute of Immunology, University of Vienna, Austria.
J Immunol. 1994 Apr 15;152(8):3720-8.
T cell activation requires Ag contact with the TCR in the presence of costimulatory signals provided by APCs. When Ag is presented without costimulation, T cells are functionally inactivated. Here we demonstrate that interference with distinct adhesion molecules during Ag contact using mAbs leads to Ag-specific functional inactivation of alloreactive T cells. We found that the presence of a mixture of mAbs specific for CD2, LFA-3, LFA-1 alpha- and beta-chain, and ICAM-1 during primary MLC leads to down-regulation of secondary proliferative responses to Ag from the donor used for priming. Cells from pretreated cultures proliferated well, however, when stimulated with Ag from third party donors, mitogens, or mitogenic CD3 mAb. Because specific reactivity could be restored by addition of IL-2 to restimulation cultures, altered secondary responsiveness appeared to be caused by anergy and not by elimination of specific clones. Furthermore, specific down-regulation of alloresponsiveness was prevented by addition of IL-2 to primary cultures in the presence of mAb. Interference by mAb with either CD2/LFA-3, LFA-1/ICAM-1, CD2/LFA-1, or LFA-3/ICAM-1 had a substantial, though less pronounced effect on secondary responsiveness. After pretreatment with the Ab mixture, CTL generation was substantially but incompletely down-regulated against the original and third party donors. Because a decrease in the reactivity of unstimulated responders by culture was also observed, these findings might be explained by the loss of cytotoxic precursors after culturing under nonstimulating conditions. In conclusion, our data demonstrate that T cells enter a state of anergy when T cell activation is modulated by simultaneous interference with distinct adhesion molecules during Ag contact, which thus might reflect at least partly overlapping functions of particular receptor-ligand pairs in T cell costimulation.
T细胞活化需要在抗原呈递细胞提供的共刺激信号存在的情况下，抗原与T细胞受体（TCR）接触。当抗原在没有共刺激的情况下呈递时，T细胞功能失活。在这里，我们证明，在抗原接触期间使用单克隆抗体干扰不同的黏附分子会导致同种反应性T细胞的抗原特异性功能失活。我们发现，在初次混合淋巴细胞培养（MLC）期间，针对CD2、淋巴细胞功能相关抗原-3（LFA-3）、淋巴细胞功能相关抗原-1α链和β链以及细胞间黏附分子-1（ICAM-1）的单克隆抗体混合物的存在会导致对用于致敏的供体抗原的二次增殖反应下调。然而，当用来自第三方供体的抗原、丝裂原或促有丝分裂的CD3单克隆抗体刺激时，预处理培养物中的细胞增殖良好。因为通过向再刺激培养物中添加白细胞介素-2（IL-2）可以恢复特异性反应性，所以二次反应性的改变似乎是由无反应性引起的，而不是由特异性克隆的消除引起的。此外，在单克隆抗体存在的情况下，向原代培养物中添加IL-2可防止同种反应性的特异性下调。单克隆抗体对CD2/LFA-3、LFA-1/ICAM-1、CD2/LFA-1或LFA-3/ICAM-1的干扰对二次反应性有显著但不太明显的影响。用抗体混合物预处理后，针对原始供体和第三方供体的细胞毒性T淋巴细胞（CTL）生成显著但不完全下调。因为在培养过程中也观察到未刺激的反应细胞的反应性降低，这些发现可能是由于在非刺激条件下培养后细胞毒性前体的丧失所致。总之，我们的数据表明，当在抗原接触期间通过同时干扰不同的黏附分子来调节T细胞活化时，T细胞进入无反应状态，这因此可能至少部分反映了特定受体-配体对在T细胞共刺激中的重叠功能。
