JAK-STAT activation contributes to cytotoxic T cell-mediated basal cell death in human chronic lung allograft dysfunction.
JAK-STAT activation contributes to cytotoxic T cell-mediated basal cell death in human chronic lung allograft dysfunction.
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DOI：
10.1172/jci.insight.167082
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发表时间：
2023-03-22
期刊：
影响因子：
8
通讯作者：
Palmer, Scott M.
中科院分区：
文献类型：
--
作者：
Khatri, Aaditya;Todd, Jamie L. .;Kelly, Fran L. .;Nagler, Andrew;Ji, Zhicheng;Jain, Vaibhav;Gregory, Simon G.;Weinhold, Kent J.;Palmer, Scott M.
慢性肺移植物功能障碍（CLAD）是肺移植受者死亡的主要原因。CLAD的临床特征是肺功能持续下降，组织学特征是发生以气道为中心的纤维化，称为闭塞性细支气管炎。目前还没有批准的治疗CLAD的疗法，其发展的机制仍然知之甚少。我们对患有CLAD的人肺受体的移植组织进行了单细胞RNA-Seq和空间转录组学分析，并进行了独立的验证研究，以确定Janus激酶信号转导和转录激活因子（JAK-STAT）信号在气道上皮细胞中的重要作用，这有助于气道特异性同种免疫损伤。具体来说，我们确定JAK-STAT信号传导的激活导致气道基底细胞（一种重要的气道上皮祖细胞群体）中主要组织相容性复合物1（MHC-I）的上调，这导致细胞毒性T细胞介导的基底细胞死亡。本研究提供了对细胞间相互作用驱动CLAD中气道中心性同种免疫损伤的机制的深入了解，提示了CLAD预防或治疗的潜在新治疗策略。
Chronic lung allograft dysfunction (CLAD) is the leading cause of death in lung transplant recipients. CLAD is characterized clinically by a persistent decline in pulmonary function and histologically by the development of airway-centered fibrosis known as bronchiolitis obliterans. There are no approved therapies to treat CLAD, and the mechanisms underlying its development remain poorly understood. We performed single-cell RNA-Seq and spatial transcriptomic analysis of explanted tissues from human lung recipients with CLAD, and we performed independent validation studies to identify an important role of Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling in airway epithelial cells that contributes to airway-specific alloimmune injury. Specifically, we established that activation of JAK-STAT signaling leads to upregulation of major histocompatibility complex 1 (MHC-I) in airway basal cells, an important airway epithelial progenitor population, which leads to cytotoxic T cell–mediated basal cell death. This study provides mechanistic insight into the cell-to-cell interactions driving airway-centric alloimmune injury in CLAD, suggesting a potentially novel therapeutic strategy for CLAD prevention or treatment.
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影响因子：
6.2
作者：
Gauthier JM;Ruiz-Pérez D;Li W;Hachem RR;Puri V;Gelman AE;Kreisel D
通讯作者：
Kreisel D
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影响因子：
3.1
作者：
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