Mesenchymal Stromal Cell Secretion of Programmed Death-1 Ligands Regulates T Cell Mediated Immunosuppression.
Mesenchymal Stromal Cell Secretion of Programmed Death-1 Ligands Regulates T Cell Mediated Immunosuppression.
复制标题
DOI：
10.1002/stem.2509
复制
发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Le Blanc K
中科院分区：
文献类型：
--
作者：
Davies LC;Heldring N;Kadri N;Le Blanc K
间充质基质细胞（MSC）发挥广泛的免疫抑制潜力，调节先天性和适应性免疫系统细胞的活性。随着MSC被接受为治疗免疫性疾病如移植物抗宿主病的治疗选择，我们需要了解它们发挥作用的复杂细节是至关重要的。程序性死亡-1（PD-1）是T细胞活化和稳态控制的重要调节因子。据报道，该途径在MSC的接触依赖性介导的免疫调节中可能是重要的。本研究的目的是确定MSC除了其细胞表面表达外，是否能够分泌PD-1配体（PD-L1和PD-L2）及其在调节MSC免疫抑制的非接触依赖性机制中的潜在重要性。在这里，我们报告了MSC表达和分泌PD-L1和PD-L2，并且这受到干扰素γ和肿瘤坏死因子α的调节。MSC通过分泌PD-1配体，抑制CD 4 + T细胞的活化，下调白细胞介素-2的分泌，并诱导不可逆的低反应性和细胞死亡。受抑制的T细胞显示T308时AKT磷酸化减少，随后FOXO 3表达增加，这可以通过阻断PD-L1逆转。总之，我们首次证明了MSC能够分泌PD-1配体，这是第一个已知的关于PD-L2在MSC中的生物学作用的报道。这些可溶性因子在调节MSC直接对T细胞行为的免疫抑制作用和诱导外周耐受中起重要作用。干细胞2017;35：766-776
Mesenchymal stromal cells (MSCs) exert broad immunosuppressive potential, modulating the activity of cells of innate and adaptive immune systems. As MSCs become accepted as a therapeutic option for the treatment of immunological disorders such as Graft versus Host Disease, our need to understand the intricate details by which they exert their effects is crucial. Programmed death‐1 (PD‐1) is an important regulator in T cell activation and homeostatic control. It has been reported that this pathway may be important in contact‐dependent mediated immunomodulation by MSCs. The aim of this study was to establish whether MSCs, in addition to their cell‐surface expression, are able to secrete PD‐1 ligands (PD‐L1 and PD‐L2) and their potential importance in modulating contact‐independent mechanisms of MSC immunosuppression. Here we report that MSCs express and secrete PD‐L1 and PD‐L2 and that this is regulated by exposure to interferon γ and tumor necrosis factor α. MSCs, via their secretion of PD‐1 ligands, suppress the activation of CD4+ T cells, downregulate interleukin‐2 secretion and induce irreversible hyporesponsiveness and cell death. Suppressed T cells demonstrated a reduction in AKT phosphorylation at T308 and a subsequent increase in FOXO3 expression that could be reversed with blockade of PD‐L1. In conclusion, we demonstrate for the first time, that MSCs are able to secrete PD‐1 ligands, with this being the first known report of a biological role for PD‐L2 in MSCs. These soluble factors play an important role in modulating immunosuppressive effects of MSCs directly on T cell behavior and induction of peripheral tolerance. Stem Cells 2017;35:766–776
登录
查看更多内容
影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
4.4
作者：
English, Karen;Barry, Frank P.;Mahon, Bernard P.
通讯作者：
Mahon, Bernard P.
用 TNF-α、IL-1β 和一氧化氮预激活间充质干细胞增强其对辐射引起的肠道损伤的旁分泌作用
影响因子：
4.6
作者：
Chen H;Min XH;Wang QY;Leung FW;Shi L;Zhou Y;Yu T;Wang CM;An G;Sha WH;Chen QK
通讯作者：
Chen QK
DOI：
10.1084/jem.20090847
发表时间：
2009-12-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Francisco LM;Salinas VH;Brown KE;Vanguri VK;Freeman GJ;Kuchroo VK;Sharpe AH
通讯作者：
Sharpe AH
影响因子：
168.9
作者：
LeBlanc, Katarina;Frassoni, Francesco;Ringden, Olle
通讯作者：
Ringden, Olle