Hargreaves R G, Borthwick N J, Gilardini Montani M S, Piccolella E, Carmichael P, Lechler R I, Akbar A N, Lombardi G
Department of Immunology, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
J Immunol. 1997 Apr 1;158(7):3099-107.
Induction of anergy and deletion due to apoptosis are two of the mechanisms involved in peripheral tolerance. To clarify the relationship between these two phenomena we have used an in vitro system of T cell Ag presentation. The recognition of Ag displayed by MHC class II-expressing T cells (T-APC) induces partial signals in Ag-specific T cell clones. This leads to a blunted intracellular calcium flux, and the T cells become unable to proliferate in response to further challenge with professional APC. These T cells are unable to produce IL-2, but retain the ability to release IL-4. In the present study, we report that for some T cell clones, the predominant outcome of Ag recognition on T cells is cell death. For susceptible T cell clones, the number of cells that die is proportional to the peptide concentration. This cell death resulted from Fas/Apo-1 (CD95)/Fas-ligand interactions between the T cells, in that Fas ligand expression was detected following overnight culture of T cells with T-APC and neutralizing anti-CD95 Ab protected from death. Most notably, following anti-CD95-mediated protection from apoptosis, the rescued T cells remained unable to respond to rechallenge with Ag-pulsed, professional APC. These data suggest that anergy and apoptosis can be separated as consequences of partial T cell signaling.
无能的诱导以及凋亡导致的清除是外周耐受所涉及的两种机制。为了阐明这两种现象之间的关系，我们使用了一个T细胞抗原呈递的体外系统。由表达MHC II类分子的T细胞（T-APC）呈递的抗原被识别后，会在抗原特异性T细胞克隆中诱导部分信号。这导致细胞内钙流减弱，并且T细胞在受到专业抗原呈递细胞的进一步刺激时无法增殖。这些T细胞无法产生白细胞介素-2，但保留释放白细胞介素-4的能力。在本研究中，我们报告对于一些T细胞克隆，抗原识别对T细胞的主要结果是细胞死亡。对于易感T细胞克隆，死亡细胞的数量与肽浓度成正比。这种细胞死亡是由T细胞之间的Fas/Apo-1（CD95）/Fas配体相互作用引起的，因为在用T-APC过夜培养T细胞后检测到了Fas配体的表达，并且中和性抗CD95抗体可保护细胞免于死亡。最值得注意的是，在抗CD95介导的对凋亡的保护之后，获救的T细胞仍然无法对用抗原脉冲处理的专业抗原呈递细胞的再次刺激做出反应。这些数据表明，无能和凋亡可以作为部分T细胞信号传导的结果而被区分开来。
