Vaknin Ilan, Blinder Liora, Wang Lynn, Gazit Roi, Shapira Elena, Genina Olga, Pines Mark, Pikarsky Eli, Baniyash Michal
Lautenberg Center for General and Tumor Immunology, Hebrew University Hadassah Medical School, Jerusalem, Israel.
Blood. 2008 Feb 1;111(3):1437-47. doi: 10.1182/blood-2007-07-100404. Epub 2007 Nov 8.
T- and natural killer (NK)-cell immunosuppression associated with zeta-chain down-regulation has been described in cancer, autoimmune, and infectious diseases. However, the precise stimuli leading to this bystander phenomenon in such different pathogen-dependent and sterile pathologies remained unresolved. Here, we demonstrate that Toll-like receptors (TLRs) play a major role in the induction of innate and adaptive immune system suppression; repetitive administration of single TLR 2, 3, 4, or 9 agonists, which do not exhibit any virulent or immune invasive properties, was sufficient to induce a bystander NK- and T-cell immunosuppression associated with zeta-chain down-regulation mediated by myeloid suppressor cells, as observed in the course of active pathologies. We identified a 35-amino acid (aa) region within the zeta-chain as being responsible for its degradation under TLR-mediated chronic inflammation. Furthermore, we provide evidence that zeta-chain levels could serve as a biomarker for chronic inflammation-dependent immunosuppression. Thus, although acute TLR-mediated activation could be beneficial in clearing pathogens or may serve as an immune adjuvant, such activation could be detrimental under sustained conditions.
与ζ链下调相关的T细胞和自然杀伤（NK）细胞免疫抑制在癌症、自身免疫性疾病和感染性疾病中已有报道。然而，在这些不同的病原体依赖性和无菌性病理中，导致这种旁观者现象的确切刺激因素仍未得到解决。在此，我们证明Toll样受体（TLR）在诱导先天性和适应性免疫系统抑制中起主要作用；重复给予不具有任何毒性或免疫侵袭特性的单一TLR 2、3、4或9激动剂，足以诱导与髓系抑制细胞介导的ζ链下调相关的旁观者NK细胞和T细胞免疫抑制，这在活动性病理过程中可见。我们确定ζ链内一个35个氨基酸（aa）的区域是其在TLR介导的慢性炎症下发生降解的原因。此外，我们提供证据表明ζ链水平可作为慢性炎症依赖性免疫抑制的生物标志物。因此，虽然急性TLR介导的激活可能有利于清除病原体或可作为免疫佐剂，但在持续条件下这种激活可能是有害的。
