Boselli Daniela, Losana Giuliana, Bernabei Paola, Bosisio Daniela, Drysdale Pamela, Kiessling Rolf, Gaston John S H, Lammas David, Casanova Jean-Laurent, Kumararatne Dinakantha S, Novelli Francesco
Department of Medicine and Experimental Oncology, University of Turin, and Center for Experimental Research and Medical Studies, S. Giovanni Battista Hospital, Turin, Italy.
Eur J Immunol. 2007 Aug;37(8):2196-204. doi: 10.1002/eji.200636541.
Fas and Fas Ligand (FasL) expression, activation-induced cell death (AICD) and mycobacterial antigen-specific cytotoxicity of peripheral T cells from patients with complete inherited IFN-gamma receptor 1 binding chain deficiency (IFN-gammaR1-/-) were investigated. Fas was equally expressed in both normal and deficient T lymphoblasts and they underwent apoptosis when stimulated with agonist anti-Fas mAb. By contrast, T lymphoblasts and CD4+ T cell clones (TCC) from deficient patients displayed a reduced surface FasL expression and resistance to AICD. CD8+ TCC from healthy and deficient patients displayed similar high level of FasL and susceptibility to AICD. In Jurkat CD4+ T cells competent to transduce IFN-gamma signaling, IFN-gamma induced surface FasL export and their Fas-dependent apoptosis. Effector T cells generated from a patient with a dominant negative mutation of IFN-gammaR1 (IFN-gammaR1DN) following stimulation with mycobacterial antigens were unable to kill MHC class II-matched, mycobacterial antigen-pulsed macrophages. Normal Fas expression in T cells and FasL in CD8+ cells may account for the absence of autoimmune disorders in these patients. Conversely, defective FasL expression on IFN-gammaR1DN CD4+ T cells impairs their cytotoxic functions and highlights a novel role for IFN-gamma signaling in the control of mycobacterial infection in humans.
对完全遗传性γ干扰素受体1结合链缺陷（IFN-γR1-/-）患者外周血T细胞的Fas和Fas配体（FasL）表达、活化诱导的细胞死亡（AICD）以及分枝杆菌抗原特异性细胞毒性进行了研究。Fas在正常和缺陷T淋巴母细胞中表达水平相同，且在用激动型抗Fas单克隆抗体刺激时会发生凋亡。相比之下，缺陷患者的T淋巴母细胞和CD4+ T细胞克隆（TCC）表面FasL表达降低且对AICD具有抗性。健康和缺陷患者的CD8+ TCC表现出相似的高水平FasL以及对AICD的敏感性。在能够转导γ干扰素信号的Jurkat CD4+ T细胞中，γ干扰素诱导表面FasL输出及其Fas依赖性凋亡。一名具有γ干扰素受体1显性负性突变（IFN-γR1DN）的患者在受到分枝杆菌抗原刺激后产生的效应T细胞无法杀伤与MHC II类匹配、经分枝杆菌抗原脉冲处理的巨噬细胞。T细胞中正常的Fas表达以及CD8+细胞中的FasL可能解释了这些患者不存在自身免疫性疾病的原因。相反，IFN-γR1DN CD4+ T细胞上FasL表达缺陷损害了它们的细胞毒性功能，并突出了γ干扰素信号在控制人类分枝杆菌感染中的新作用。
