IL-10 Receptor Signaling Is Essential for TR1 Cell Function In Vivo.
IL-10 Receptor Signaling Is Essential for TR1 Cell Function In Vivo.
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IL-10受体信号传导对于体内TR1细胞功能至关重要。
DOI：
10.4049/jimmunol.1601045
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发表时间：
2017-02-01
期刊：
影响因子：
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通讯作者：
Huber S
中科院分区：
文献类型：
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作者：
Brockmann L;Gagliani N;Steglich B;Giannou AD;Kempski J;Pelczar P;Geffken M;Mfarrej B;Huber F;Herkel J;Wan YY;Esplugues E;Battaglia M;Krebs CF;Flavell RA;Huber S
白细胞介素-10（IL-10）是维持肠道内稳态所必需的。CD 4 + T调节1型（TR 1）细胞产生大量的这种细胞因子，因此目前正在临床试验中作为炎症性肠病（IBD）患者的T细胞疗法进行检查。然而，维持TR 1细胞调节活性的因素和分子信号仍需要鉴定，以优化这些试验的效率并确保其安全性。我们研究了IL-10信号在体内成熟TR 1细胞中的作用。使用双IL-10 eGFP Foxp 3 mRFP报告小鼠和IL-10受体信号传导受损的转基因小鼠来测试TR 1细胞在鼠IBD模型中的活性，该模型类似于在人中进行的试验。在体外阐明了分子信号传导。最后，我们使用目前用于细胞治疗的人TR 1细胞来证实我们的结果。我们发现小鼠TR 1细胞表达功能性IL-10受体α。IL-10受体信号转导受损的TR 1细胞在体内失去了它们的调节活性。TR 1细胞需要IL-10受体信号以激活p38 MAP激酶，从而维持IL-10的产生，最终介导其抑制活性。最后，我们使用人类TR 1细胞证实了这些数据。总之，TR 1细胞调节活性依赖于IL-10受体信号传导。这些数据表明，为了优化基于TR 1细胞的治疗，必须考虑IL-10受体表达。
Interleukin-10 (IL-10) is essential to maintain intestinal homeostasis. CD4+ T regulatory type 1 (TR1) cells produce large amounts of this cytokine and being therefore currently examined in clinical trials as T-cell therapy in patients with inflammatory bowel disease (IBD). However, factors and molecular signals sustaining TR1 cell regulatory activity still need to be identified in order to optimize the efficiency and to ensure the safety of these trials. We investigated the role of IL-10 signaling in mature TR1 cells in vivo. Double IL-10eGFP Foxp3mRFP reporter mice and transgenic mice with impairment in IL-10 receptor signaling were used to test the activity of TR1 cells in a murine IBD model, a model that resembles the trials performed in humans. The molecular signaling was elucidated in vitro. Finally, we used human TR1 cells, currently employed for cell therapy, to confirm our results. We found that murine TR1 cells expressed functional IL-10 receptor α. TR1 cells with impaired IL-10 receptor signaling lost their regulatory activity in vivo. TR1 cells required IL-10 receptor signaling in order to activate p38 MAP kinase, thereby sustaining IL-10 production, which ultimately mediated their suppressive activity. Finally, we confirmed these data using human TR1 cells. In conclusion TR1 cell regulatory activity is dependent on IL-10 receptor signaling. These data suggest that in order to optimize TR1 cell-based therapy, IL-10 receptor expression has to be taken into consideration.