Growth Factor Receptor Bound Protein 2–Associated Binder 2, a Scaffolding Adaptor Protein, Negatively Regulates Host Immunity against Tuberculosis
| Autor: | Yan Zhang, Shizong Hu, Haiying Liu, Yuehai Ke, Yang Yu, Zongde Zhang, Hongyan Jia, Dongdong Jin, Shuxiang Gu, Xinchun Chen, Qi Jin, Xue Zhang |
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| Rok vydání: | 2014 |
| Předmět: |
Pulmonary and Respiratory Medicine
Time Factors Tuberculosis Clinical Biochemistry GAB1 GATA3 Transcription Factor Biology Proinflammatory cytokine Mycobacterium tuberculosis Mice Growth factor receptor Gene expression medicine Animals Humans RNA Messenger Lung Tuberculosis Pulmonary Molecular Biology Adaptor Proteins Signal Transducing Mice Knockout Immunity Cellular Cell Biology Growth Factor Receptor-Bound Protein 2 Phosphoproteins biology.organism_classification medicine.disease Bacterial Load Disease Models Animal Case-Control Studies Host-Pathogen Interactions Immunology Cytokine secretion Inflammation Mediators TCF Transcription Factors |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 51:575-585 |
| ISSN: | 1535-4989 1044-1549 |
| DOI: | 10.1165/rcmb.2013-0329oc |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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