Allergen-specific lung-resident Tregs in asthma: Targetable suppressors of resident memory Th2 cells

哮喘中过敏原特异性肺常驻 Tregs：常驻记忆 Th2 细胞的靶向抑制因子

• 批准号: 10418189
• 负责人: ANDREW D LUSTER
• 金额: $ 60.02万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-04 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10418189
• 关键词: Adoptive Transfer; Allergens; Allergic; Allergic inflammation; Anatomy; Antigens; Asthma; Bone Marrow; CCL1 gene; CCL8 gene; CCR8 gene; CD4 Positive T Lymphocytes; CXCR6 gene; Cells; Chronic Disease; Effector Cell; Exhibits; Extrinsic asthma; FOXP3 gene; Failure; Flow Cytometry; Frequencies; Generations; Genetic Transcription; Goals; Human; Immune response; Immune system; Immunohistochemistry; Immunosuppressive Agents; In Vitro; Individual; Inflammation; Inhalation; Lead; Ligands; Location; Lung; MUC5AC gene; Maintenance; Mediating; Memory; Metaplasia; Modeling; Mucins; Mucous body substance; Mus; Pattern; Peptides; Phenotype; Play; Population; Positioning Attribute; Prevalence; Production; Proliferating; Pulmonary Inflammation; Pyroglyphidae; Regulatory T-Lymphocyte; Reporter; Residencies; Resolution; Role; Specificity; Surface; System; T memory cell; Testing; Th2 Cells; Therapeutic; Time; Tissues; Transgenic Organisms; Up-Regulation; airborne allergen; airway hyperresponsiveness; airway immune response; airway inflammation; allergic response; asthma model; chemokine; chemokine receptor; chronic inflammatory disease; cost estimate; cytokine; environmental allergen; eosinophil; experimental study; novel therapeutic intervention; programs; response; single-cell RNA sequencing; transcriptome sequencing; treatment strategy

Asthma is one of the most common chronic diseases and it is still on the rise with a prevalence of ~8% of the U.S. population and an estimated cost of $82 billion/year. New therapeutic approaches are needed that offer the potential for a long-lasting cure. Allergic asthma is the most common endotype and is thought to be driven in large part by a type 2 airway immune response to inhaled allergens. Foxp3+ regulatory T cells (Tregs) are potent suppressors of immune responses and are an attractive target to treat allergic asthma. The CD4+ T helper type 2 (Th2)-mediated response to environmental allergens that drives allergic asthma is thought to be due to an imbalance between allergen-specific effector and regulatory responses. Recent studies by us and others have demonstrated that resident memory (Trm) Th2 cells that reside in the lung are key effector cells that drive many of the features of allergic asthma. Th2-Trm cells proliferate near airways following allergen challenge and are responsible for inducing mucus metaplasia, airway hyperresponsiveness, and airway eosinophil activation. While memory T cells were believed to continually re-circulate within the host, it has recently become clear that Trm remain anatomically positioned to initiate antigen-specific immune responses at barrier surfaces. In preliminary studies, we have now found that allergen-specific Tregs also reside in the lung following aeroallergen sensitization and are the key cell that suppresses the Th2-Trm response. This has led us to the central hypothesis of this proposal that resident (r) Treg suppression of Th2-Trm is key to regulating the allergic asthma phenotype. Th2-Trm exhibit a distinct transcriptional program that includes the upregulation of the chemokine receptors CCR8 and CXCR6. In preliminary studies, we have found rTregs in the lung also upregulate CCR8 and CXCR6 during a type 2 response. This has led us to hypothesize that the CCR8 and CXCR6 chemokine systems play roles in the tissue residency programs of Tregs and their ability to be juxtaposed to Th2-Trm around the airways. The central hypothesis of this proposal will also be explored in humans with allergic asthma. Our group has investigated the response to bronchoscopic segmental allergen challenge in humans with allergic asthma (AA) and allergic non-asthmatic controls (ANA). We found increased airway type 2 cytokine production, total mucin, and mucin MUC5AC in response to allergen in AA compared to ANA subjects. These findings suggest that differences in the activation of Th2-Trm within the airways may be critical for allergen-sensitized individuals to develop the asthma phenotype. We will test the hypothesis that differences in relative frequency, phenotype and/or TCR specificities of rTregs in the lung underly the differences in the response to aeroallergen in ANA and AA subjects. Specifically, we propose to: (1) Further define the role of lung rTregs in suppressing Th2-Trm; (2) Determine the role of the CCR8 and CXCR6 chemokine systems in the tissue residency program positioning and function of rTregs in the allergic lung; and (3) Extend these studies to humans by comparing the numbers, phenotype and TCR specificities of rTregs in AA and ANA subjects.

哮喘是最常见的慢性病之一，其患病率仍在上升，约占 美国人口和估计成本为820亿美元/年。需要新的治疗方法来提供 可能会有持久的治愈方法。过敏性哮喘是最常见的内型，被认为是由 很大程度上是由2型呼吸道对吸入性变应原的免疫反应所致。Foxp3+调节性T细胞(Treg)是有效的 免疫反应的抑制物，是治疗过敏性哮喘的有吸引力的靶点。CD4+T细胞辅助型 2(Th2)介导的对环境过敏原的反应导致过敏性哮喘被认为是由于 过敏原特异性效应因子和调节反应之间的不平衡。我们和其他人最近的研究表明 证明了驻留在肺中的驻留记忆(Trm)Th2细胞是驱动许多 过敏性哮喘的特征。Th2-Trm细胞在过敏原攻击后在呼吸道附近增殖，并 负责诱导粘液化生、气道高反应性和气道嗜酸性粒细胞激活。而当 记忆T细胞被认为在宿主内不断地重新循环，最近发现Trm 保持解剖位置，在屏障表面启动抗原特异性免疫反应。在预赛中 研究表明，我们现在发现，在空气变应原作用下，变应原特异的Treg也存在于肺中。 是抑制Th2-Trm反应的关键细胞。这就把我们带到了中央 这一假设认为，Th2-Trm的常驻(R)Treg抑制是调节过敏性哮喘的关键 表型。Th2-Trm表现出一个独特的转录程序，其中包括趋化因子的上调 受体CCR8和CXCR6。在初步研究中，我们发现肺中的rTregs也上调CCR8 以及类型2响应期间的CXCR6。这导致我们假设CCR8和CXCR6趋化因子 系统在Tregs的组织驻留计划中发挥作用，以及它们与Th2-Trm并列的能力 航空公司。这一建议的中心假设也将在患有过敏性哮喘的人类身上进行探索。我们的 研究小组调查了过敏症患者对支气管镜检查节段性变应原挑战的反应 哮喘(AA)和过敏性非哮喘对照(ANA)。我们发现呼吸道2型细胞因子产生增加， 与ANA受试者相比，AA患者总粘蛋白和粘蛋白MUC5AC对变应原的反应。这些发现 提示呼吸道内Th2-Trm激活的差异可能是过敏原致敏的关键因素 个体发展为哮喘表型。我们将检验一个假设，即相对频率的差异， 肺内rTregs的表型和/或TCR特异性低于对空气变应原反应的差异 ANA和AA受试者。具体地说，我们建议：(1)进一步定义肺rTregs在抑制 Th2-Trm；(2)确定CCR8和CXCR6趋化因子系统在组织驻留计划中的作用 RTregs在过敏肺中的定位和功能；以及(3)通过比较rTregs在过敏肺中的作用，将这些研究扩展到人类 再生障碍性贫血和再生障碍性贫血患者rTregs的数量、表型和TCR特异性。