过敏性致敏损害肺部常驻记忆CD8 T细胞反应和病毒清除
2022/08/19
摘要
背景：哮喘患者经常遭受频繁的呼吸道病毒的感染和病毒清除率的降低。肺部常驻记忆T细胞能迅速保护患者免受病毒再感染。
目的：由于常驻记忆T细胞的发展依赖于肺部微环境，我们调查了过敏原致敏对病毒特异性肺部常驻记忆T细胞发展和病毒清除的影响。
方法：用屋尘螨提取物使小鼠致敏，然后用X47引发，随后进行继发性流感感染。在继发性流感感染之前和之后，分别评估抗病毒记忆T细胞反应和对病毒感染的保护作用。对U-BIOPRED哮喘队列的数据集进行基因组变异分析，使用IFNγ诱导上皮细胞特征和组织常驻记忆T细胞特征。
结果：与非致敏小鼠相比，致敏小鼠在二次感染后肺部的病毒载量更高，表明病毒清除率降低。X47引物诱导较少的抗病毒肺部常驻记忆CD8 T细胞，且与非致敏小鼠相比，致敏小鼠的肺部IFNγ水平较低。利用U-BIOPRED队列的数据，我们发现在鼻刷和支气管活检中上皮IFNγ诱导基因富集的患者，也表现出TRM相关基因的富集，同时具有更多的上皮CD8 T细胞，并且报告的病情恶化明显减少。
结论：过敏原致敏的肺部微环境干扰了肺部抗病毒常驻记忆CD8 T细胞的形成和病毒清除。抗病毒记忆反应的缺陷可能会增加哮喘患者对病毒恶化的易感性。
Allergic sensitisation impairs lung resident memory CD8 T cell response and virus clearance.
Agrawal, K., Ong, L. C., Monkley, S., Thörn, K., Israelsson, E., Baturcam, E., Rist, C., Schön, K., Blake, S., Magnusson, B., Cartwright, J., Mitra, S., Ravi, A., Zounemat-Kermani, N., Krishnaswamy, J. K., Lycke, N. Y., Gehrmann, U., Mattsson, J., & U-BIOPRED study group
Abstract
BACKGROUND：Asthma patients often suffer from frequent respiratory viral infections and reduced virus clearance. Lung resident memory T cells provide rapid protection against viral re-infections.
OBJECTIVE：As development of resident memory T cells relies on the lung microenvironment, we investigated the impact of allergen sensitisation on the development of virus-specific lung resident memory T cells and viral clearance.
METHODS：Mice were sensitised with house dust mite extract followed by priming with X47 and a subsequent secondary influenza infection. Anti-viral memory T cell responses and protection to viral infection was assessed pre- and post-secondary influenza infection, respectively. Gene set variation analysis was performed on datasets from U-BIOPRED asthma cohort using an IFNү-induced epithelial cell signature and a tissue resident memory T cell signature.
RESULTS：Viral loads were higher in lungs of sensitised compared to non-sensitised mice post-secondary infection, indicating reduced virus clearance. X47 priming induced fewer anti-viral lung resident memory CD8 T cells and resulted in lower pulmonary IFNү levels in the lungs of sensitised as compared to non-sensitised mice. Using data from the U-BIOPRED cohort, we found that patients with enrichment of epithelial IFNү-induced genes in nasal brushings and bronchial biopsies were also enriched in TRM associated genes, had more epithelial CD8 T cells and reported significantly fewer exacerbations.
CONCLUSION：The allergen sensitised lung microenvironment interferes with the formation of anti-viral resident memory CD8 T cells in lungs and virus clearance. Defective anti-viral memory response might contribute to increased susceptibility of asthma patients to viral exacerbations.
背景：哮喘患者经常遭受频繁的呼吸道病毒的感染和病毒清除率的降低。肺部常驻记忆T细胞能迅速保护患者免受病毒再感染。
目的：由于常驻记忆T细胞的发展依赖于肺部微环境，我们调查了过敏原致敏对病毒特异性肺部常驻记忆T细胞发展和病毒清除的影响。
方法：用屋尘螨提取物使小鼠致敏，然后用X47引发，随后进行继发性流感感染。在继发性流感感染之前和之后，分别评估抗病毒记忆T细胞反应和对病毒感染的保护作用。对U-BIOPRED哮喘队列的数据集进行基因组变异分析，使用IFNγ诱导上皮细胞特征和组织常驻记忆T细胞特征。
结果：与非致敏小鼠相比，致敏小鼠在二次感染后肺部的病毒载量更高，表明病毒清除率降低。X47引物诱导较少的抗病毒肺部常驻记忆CD8 T细胞，且与非致敏小鼠相比，致敏小鼠的肺部IFNγ水平较低。利用U-BIOPRED队列的数据，我们发现在鼻刷和支气管活检中上皮IFNγ诱导基因富集的患者，也表现出TRM相关基因的富集，同时具有更多的上皮CD8 T细胞，并且报告的病情恶化明显减少。
结论：过敏原致敏的肺部微环境干扰了肺部抗病毒常驻记忆CD8 T细胞的形成和病毒清除。抗病毒记忆反应的缺陷可能会增加哮喘患者对病毒恶化的易感性。
(中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2022 Jul 30; DOI: 10.1016/j.jaci.2022.07.004)
(J Allergy Clin Immunol. 2022 Jul 30; DOI: 10.1016/j.jaci.2022.07.004)
Allergic sensitisation impairs lung resident memory CD8 T cell response and virus clearance.
Agrawal, K., Ong, L. C., Monkley, S., Thörn, K., Israelsson, E., Baturcam, E., Rist, C., Schön, K., Blake, S., Magnusson, B., Cartwright, J., Mitra, S., Ravi, A., Zounemat-Kermani, N., Krishnaswamy, J. K., Lycke, N. Y., Gehrmann, U., Mattsson, J., & U-BIOPRED study group
Abstract
BACKGROUND：Asthma patients often suffer from frequent respiratory viral infections and reduced virus clearance. Lung resident memory T cells provide rapid protection against viral re-infections.
OBJECTIVE：As development of resident memory T cells relies on the lung microenvironment, we investigated the impact of allergen sensitisation on the development of virus-specific lung resident memory T cells and viral clearance.
METHODS：Mice were sensitised with house dust mite extract followed by priming with X47 and a subsequent secondary influenza infection. Anti-viral memory T cell responses and protection to viral infection was assessed pre- and post-secondary influenza infection, respectively. Gene set variation analysis was performed on datasets from U-BIOPRED asthma cohort using an IFNү-induced epithelial cell signature and a tissue resident memory T cell signature.
RESULTS：Viral loads were higher in lungs of sensitised compared to non-sensitised mice post-secondary infection, indicating reduced virus clearance. X47 priming induced fewer anti-viral lung resident memory CD8 T cells and resulted in lower pulmonary IFNү levels in the lungs of sensitised as compared to non-sensitised mice. Using data from the U-BIOPRED cohort, we found that patients with enrichment of epithelial IFNү-induced genes in nasal brushings and bronchial biopsies were also enriched in TRM associated genes, had more epithelial CD8 T cells and reported significantly fewer exacerbations.
CONCLUSION：The allergen sensitised lung microenvironment interferes with the formation of anti-viral resident memory CD8 T cells in lungs and virus clearance. Defective anti-viral memory response might contribute to increased susceptibility of asthma patients to viral exacerbations.
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