T-cell restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung
T-cell restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung
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DOI：
10.1182/blood-2014-05-575225
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发表时间：
2015-01-08
期刊：
影响因子：
20.3
通讯作者：
Ishii, Yukio
中科院分区：
文献类型：
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作者：
Iriguchi, Shoichi;Kikuchi, Norihiro;Ishii, Yukio
虽然T-bet（1型辅助性T淋巴细胞中的主要转录因子）的过表达已在几种血液和免疫疾病中报道，但其在其发病机制中的作用尚未完全了解。在本研究中，我们使用转基因模型小鼠（T-bet（tg/wt）和T-bet（tg/tg））来研究T-bet在T淋巴细胞中选择性过表达对血液学和免疫疾病发生的影响。结果表明，T-bet在T细胞中的过表达自发地诱导单核吞噬细胞谱系的成熟停滞，以及分别在T-bet（tg/wt）和d T-bet（tg/tg）小鼠中的自发性皮炎和肺泡蛋白沉积症（PAP）样疾病。具有PAP表型的T-bet（tg/tg）肺泡显示出肺泡单核吞噬细胞亚群的显着重组和功能受损，以及T细胞浸润的增加。此外，发现T-be（tg/tg）小鼠中的PAP发展与髓样细胞从骨髓向外周血的迁移增加相关。这些发现揭示了T淋巴细胞中T-bet过度表达与肺中单核吞噬细胞重组引起的PAP发展之间的意外联系，并为继发性PAP伴血液系统疾病的分子发病机制提供了新的见解。
Although overexpression of T-bet, a master transcription factor in type-1 helper T lymphocytes, has been reported in several hematologic and immune diseases, its role in their pathogenesis is not fully understood. In the present study, we used transgenic model mice(T-bet(tg/wt) and T-bet(tg/tg))to investigate the effects of T-bet overexpression selectively in T lymphocytes on the development of hematologic and immune diseases. The results showed that T-bet overexpression in T cells spontaneously induced maturation arrest in the mononuclear phagocyte lineage, as well as spontaneous dermatitis and pulmonary alveolar proteinosis (PAP)-like disease in T-bet(tg/wt) an d T-bet(tg/tg) mice, respectively. T-bet(tg/tg) alveoli with the PAP phenotype showed remarkable reorganization of alveolar mononuclear phagocyte subpopulations and impaired function, in addition to augmented T-cell infiltration. In addition, PAP development in T-be(tg/tg) mice was found to be associated with increased migration of myeloid cells from the bone marrow into the peripheral blood. These findings reveal an unexpected link between T-bet overexpression in T lymphocytes and the development of PAP caused by reorganization of mononuclear phagocytes in the lung, and provide new insight into the molecular pathogenesis of secondary PAP accompanied by hematologic disorders.