LAIR-1作为活化的ILC2s的免疫检查点，可调节气道高反应性的诱导
2021/08/24
摘要
背景：2型先天淋巴样细胞(ILC2s)是2型哮喘的相关参与者。它们通过细胞因子的分泌引起嗜酸性粒细胞浸润和气道高反应性(AHR)。白细胞相关免疫球蛋白样受体1 (LAIR-1)是一种抑制性受体，被认为是不同炎症性疾病的免疫检查点。
目的：我们的目的是研究LAIR-1的表达，并评估其在人类和小鼠ILC2s中的作用。
方法：将野生型和LAIR-1敲除小鼠经鼻内注射IL-33，并将肺ILC2s分选，基于RNA测序和流式细胞术进行离体比较研究。接下来，我们通过敲除小鼠和Rag22/ 2Il2rg2/2小鼠过继转移实验研究了LAIR-1缺乏对AHR和肺炎症的影响。利用敲低反义策略和人源小鼠来评估LAIR-1在人ILC2s中的作用。
结果：我们已经证实，LAIR-1可诱导激活的ILC2s，并下调细胞因子的分泌和效应功能。在IL-33和互交链孢菌模型中，ILC2s中的LAIR-1信号通过抑制途径(包括SHP1/PI3K/AKT)介导，而LAIR-1的缺失导致ILC2依赖的AHR加剧。在过继转移实验中，我们证实了LAIR-1介导的ILC2s在体内的调节作用。有趣的是，LAIR-1在人ILC2s中表达并可诱导，而敲低LAIR-1的方法会导致更高的细胞因子的产生。最后，在人源化ILC2小鼠模型中，生理配体C1q与LAIR-1的结合显著降低了ILC2依赖性AHR。
结论：我们的研究结果揭示了ILC2s的一个新的调节轴，该轴具有降低过敏性AHR和肺部炎症的能力。
LAIR-1 acts as an immune checkpoint on activated ILC2s and regulates the induction of airway hyperreactivity
Helou DG, Shafiei-Jahani P, Hurrell BP, et al.
Abstract
BACKGROUND:Type 2 innate lymphoid cells (ILC2s) are relevant players in type 2 asthma. They initiate eosinophil infiltration and airway hyperreactivity (AHR) through cytokine secretion. Leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is an inhibitory receptor considered to be an immune checkpoint in different inflammatory diseases.
OBJIECTIVE:Our aim here was to investigate the expression of LAIR-1 and assess its role in human and murine ILC2s.
METHODS:Wild-type and LAIR-1 knockout mice were intranasally challenged with IL-33, and pulmonary ILC2s were sorted to perform an ex vivo comparative study based on RNA sequencing and flow cytometry. We next studied the impact of LAIR-1 deficiency on AHR and lung inflammation by using knockout mice and adoptive transfer experiments in Rag22/ 2Il2rg2/2 mice. Knockdown antisense strategies and humanized mice were used to assess the role of LAIR-1 in human ILC2s. Results: We have demonstrated that LAIR-1 is inducible on activated ILC2s and downregulates cytokine secretion and effector function. LAIR-1 signaling in ILC2s was mediated via inhibitory pathways, including SHP1/PI3K/AKT, and LAIR-1 deficiency led to exacerbated ILC2-dependent AHR in IL-33 and Alternaria alternata models. In adoptive transfer experiments, we confirmed the LAIR-1–mediated regulation of ILC2s in vivo. Interestingly, LAIR-1 was expressed and inducible in human ILC2s, and knockdown approaches of Lair1 resulted in higher cytokine production. Finally, engagement of LAIR-1 by physiologic ligand C1q significantly reduced ILC2-dependent AHR in a humanized ILC2 murine model.
CONLUSIONS:Our results unravel a novel regulatory axis in ILC2s with the capacity to reduce allergic AHR and lung inflammation.
背景：2型先天淋巴样细胞(ILC2s)是2型哮喘的相关参与者。它们通过细胞因子的分泌引起嗜酸性粒细胞浸润和气道高反应性(AHR)。白细胞相关免疫球蛋白样受体1 (LAIR-1)是一种抑制性受体，被认为是不同炎症性疾病的免疫检查点。
目的：我们的目的是研究LAIR-1的表达，并评估其在人类和小鼠ILC2s中的作用。
方法：将野生型和LAIR-1敲除小鼠经鼻内注射IL-33，并将肺ILC2s分选，基于RNA测序和流式细胞术进行离体比较研究。接下来，我们通过敲除小鼠和Rag22/ 2Il2rg2/2小鼠过继转移实验研究了LAIR-1缺乏对AHR和肺炎症的影响。利用敲低反义策略和人源小鼠来评估LAIR-1在人ILC2s中的作用。
结果：我们已经证实，LAIR-1可诱导激活的ILC2s，并下调细胞因子的分泌和效应功能。在IL-33和互交链孢菌模型中，ILC2s中的LAIR-1信号通过抑制途径(包括SHP1/PI3K/AKT)介导，而LAIR-1的缺失导致ILC2依赖的AHR加剧。在过继转移实验中，我们证实了LAIR-1介导的ILC2s在体内的调节作用。有趣的是，LAIR-1在人ILC2s中表达并可诱导，而敲低LAIR-1的方法会导致更高的细胞因子的产生。最后，在人源化ILC2小鼠模型中，生理配体C1q与LAIR-1的结合显著降低了ILC2依赖性AHR。
结论：我们的研究结果揭示了ILC2s的一个新的调节轴，该轴具有降低过敏性AHR和肺部炎症的能力。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（J Allergy Clin Immunol, 2021.）
（J Allergy Clin Immunol, 2021.）
LAIR-1 acts as an immune checkpoint on activated ILC2s and regulates the induction of airway hyperreactivity
Helou DG, Shafiei-Jahani P, Hurrell BP, et al.
Abstract
BACKGROUND:Type 2 innate lymphoid cells (ILC2s) are relevant players in type 2 asthma. They initiate eosinophil infiltration and airway hyperreactivity (AHR) through cytokine secretion. Leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is an inhibitory receptor considered to be an immune checkpoint in different inflammatory diseases.
OBJIECTIVE:Our aim here was to investigate the expression of LAIR-1 and assess its role in human and murine ILC2s.
METHODS:Wild-type and LAIR-1 knockout mice were intranasally challenged with IL-33, and pulmonary ILC2s were sorted to perform an ex vivo comparative study based on RNA sequencing and flow cytometry. We next studied the impact of LAIR-1 deficiency on AHR and lung inflammation by using knockout mice and adoptive transfer experiments in Rag22/ 2Il2rg2/2 mice. Knockdown antisense strategies and humanized mice were used to assess the role of LAIR-1 in human ILC2s. Results: We have demonstrated that LAIR-1 is inducible on activated ILC2s and downregulates cytokine secretion and effector function. LAIR-1 signaling in ILC2s was mediated via inhibitory pathways, including SHP1/PI3K/AKT, and LAIR-1 deficiency led to exacerbated ILC2-dependent AHR in IL-33 and Alternaria alternata models. In adoptive transfer experiments, we confirmed the LAIR-1–mediated regulation of ILC2s in vivo. Interestingly, LAIR-1 was expressed and inducible in human ILC2s, and knockdown approaches of Lair1 resulted in higher cytokine production. Finally, engagement of LAIR-1 by physiologic ligand C1q significantly reduced ILC2-dependent AHR in a humanized ILC2 murine model.
CONLUSIONS:Our results unravel a novel regulatory axis in ILC2s with the capacity to reduce allergic AHR and lung inflammation.
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