Transforming growth factor beta induces fibroblasts to express and release the immunomodulatory protein PD-L1 into extracellular vesicles
Transforming growth factor beta induces fibroblasts to express and release the immunomodulatory protein PD-L1 into extracellular vesicles
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DOI：
10.1096/fj.201902354r
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发表时间：
2020-02-01
期刊：
影响因子：
4.8
通讯作者：
Leof, Edward B.
中科院分区：
文献类型：
--
作者：
Kang, Jeong-Han;Jung, Mi-Yeon;Leof, Edward B.
转化生长因子-β（TGF β）是一种神秘的蛋白质，在健康组织稳态/发育以及癌症、伤口愈合、纤维化病症和免疫调节的发展或进展中具有各种作用，仅举几例。由于TGF β是以局部或全身组织/器官纤维化为特征的各种纤维增生性疾病以及在各种恶性肿瘤中观察到的活化基质的原因，因此表征介导其作用的途径和参与者是至关重要的。在目前的研究中，我们发现TGF β以Smad 2/3和雅普/TAZ依赖的方式诱导人和鼠成纤维细胞中免疫抑制分子PD-L1的表达。此外，PD-L1敲低降低了细胞外基质蛋白（包括胶原蛋白I α 1（colI α 1）和α-平滑肌肌动蛋白（α-SMA））的TGF β依赖性诱导，以及细胞迁移/伤口愈合。除了PD-L1在促纤维化TGF β信号传导中的内源性作用外，TGF β刺激人肺成纤维细胞来源的PD-L1进入细胞外囊泡（EV），能够抑制T细胞增殖以响应T细胞受体刺激并介导成纤维细胞迁移。这些发现为各种纤维化和恶性疾病提供了新的见解和潜在的靶点。
Transforming growth factor-beta (TGF beta) is an enigmatic protein with various roles in healthy tissue homeostasis/development as well as the development or progression of cancer, wound healing, fibrotic disorders, and immune modulation, to name a few. As TGF beta is causal to various fibroproliferative disorders featuring localized or systemic tissue/organ fibrosis as well as the activated stroma observed in various malignancies, characterizing the pathways and players mediating its action is fundamental. In the current study, we found that TGF beta induces the expression of the immunoinhibitory molecule Programed death-ligand 1 (PD-L1) in human and murine fibroblasts in a Smad2/3- and YAP/TAZ-dependent manner. Furthermore, PD-L1 knockdown decreased the TGF beta-dependent induction of extracellular matrix proteins, including collagen I alpha 1 (colI alpha 1) and alpha-smooth muscle actin (alpha-SMA), and cell migration/wound healing. In addition to an endogenous role for PD-L1 in profibrotic TGF beta signaling, TGF beta stimulated-human lung fibroblast-derived PD-L1 into extracellular vesicles (EVs) capable of inhibiting T cell proliferation in response to T cell receptor stimulation and mediating fibroblast cell migration. These findings provide new insights and potential targets for a variety of fibrotic and malignant diseases.