1 Ministry of Health (MOH) Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Am J Respir Cell Mol Biol. 2014 Oct;51(4):575-85. doi: 10.1165/rcmb.2013-0329OC.
Cell-mediated immunity is indispensable for host protection against tuberculosis (TB). Growth factor receptor bound protein 2-associated binder (Gab) 2, a scaffolding adaptor protein, negatively regulates signaling pathways critical for T cell-mediated immunity. We sought to investigate the clinical significance and immunological role of Gab2 in Mycobacterium tuberculosis infection. We evaluated Gab2 protein and messenger RNA (mRNA) expression in human patients with pulmonary TB and determined the correlation of the mRNA expression pattern with antigen-specific IFN-γ secretion. Subsequently, we carried out M. tuberculosis infection in Gab2-deficient and wild-type control mice to explore the immunological role of Gab2 by examining bacterial load, histological changes, cytokine secretion, and gene expression of immune-associated transcription factors. mRNA levels of Gab2 and its correlated family member, Gab1, were markedly decreased in untreated patients with pulmonary TB compared with healthy control subjects. Importantly, this decreased Gab2 expression to normal levels after bacterial load in the patient's sputum became undetectable under the standard anti-TB treatment, which negatively correlated with the level of M. tuberculosis antigen-specific IFN-γ secretion. In the M. tuberculosis infection mouse model, infected Gab2-deficient mice exhibited decreased bacterial load and milder lung pathological damage compared with infected wild-type mice, accompanied by decreased production of IL-2, IL-6, and granulocyte/macrophage colony-stimulating factor proinflammatory cytokines, and an increased T-cell-specific T-box transcription factor/GATA binding protein 3 expression ratio. Overall, our study indicates that down-regulation of Gab2 relates to a protective function during M. tuberculosis infection, revealing a potential negative regulatory role for Gab2 in immunity to TB.
细胞介导的免疫对于宿主抵抗结核病(TB)至关重要。生长因子受体结合蛋白 2 相关结合物(Gab)2 是一种支架衔接蛋白,可负调控对 T 细胞介导的免疫至关重要的信号通路。我们试图研究 Gab2 在结核分枝杆菌感染中的临床意义和免疫学作用。我们评估了人肺结核患者中 Gab2 蛋白和信使 RNA(mRNA)的表达,并确定了 mRNA 表达模式与抗原特异性 IFN-γ分泌之间的相关性。随后,我们在 Gab2 缺陷型和野生型对照小鼠中进行了结核分枝杆菌感染,通过检查细菌载量、组织学变化、细胞因子分泌和免疫相关转录因子的基因表达,来探讨 Gab2 的免疫学作用。未经治疗的肺结核患者的 Gab2 mRNA 水平及其相关家族成员 Gab1 的表达水平明显低于健康对照组。重要的是,在患者痰中的细菌载量变得无法检测到后,经过标准的抗结核治疗,Gab2 表达恢复至正常水平,这与结核分枝杆菌抗原特异性 IFN-γ分泌水平呈负相关。在结核分枝杆菌感染的小鼠模型中,与感染野生型小鼠相比,感染 Gab2 缺陷型小鼠的细菌载量降低,肺部病理损伤减轻,伴随 IL-2、IL-6 和粒细胞/巨噬细胞集落刺激因子促炎细胞因子的产生减少,以及 T 细胞特异性 T 盒转录因子/GATA 结合蛋白 3 表达比值增加。总体而言,我们的研究表明,Gab2 的下调与结核分枝杆菌感染期间的保护功能有关,揭示了 Gab2 在结核病免疫中的潜在负调控作用。