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疾病之一，并且其患病率仍在上升，约占世界人口的8%。 美国人口和估计成本为820亿美元/年。需要新的治疗方法， 有可能长期治愈过敏性哮喘是最常见的内型哮喘， 很大程度上是由于对吸入过敏原的2型气道免疫反应。Foxp 3+调节性T细胞（TCFs）是有效的 免疫应答的抑制因子，并且是治疗过敏性哮喘的有吸引力的靶点。CD 4 + T辅助细胞类型 2（Th 2）介导的对环境过敏原的反应驱动过敏性哮喘被认为是由于 过敏原特异性效应物和调节反应之间的不平衡。我们和其他人最近的研究 研究表明，驻留在肺中的驻留记忆（Trm）Th 2细胞是驱动许多细胞的关键效应细胞。 过敏性哮喘的特征。过敏原激发后，Th 2-Trm细胞在呼吸道附近增殖，并且 负责诱导粘液化生、气道高反应性和气道嗜酸性粒细胞活化。而 记忆T细胞被认为在宿主体内不断再循环，最近已经清楚Trm 保持解剖学定位以在屏障表面引发抗原特异性免疫应答。初步 研究，我们现在发现，过敏原特异性THBE也存在于肺后，空气过敏原 Th 2-Trm是一种重要的细胞因子，是抑制Th 2-Trm应答的关键细胞。这把我们带到了 该假说认为，Th 2-Trm的常驻（r）Treg抑制是调节过敏性哮喘的关键 表型Th 2-Trm表现出独特的转录程序，包括趋化因子的上调 受体CCR 8和CXCR 6。在初步的研究中，我们发现肺中的rT细胞也上调CCR 8， 和CXCR 6在2型反应期间。这使我们假设CCR 8和CXCR 6趋化因子 系统发挥作用的组织驻留程序的THEX和他们的能力并列的Th 2-Trm周围 呼吸道该建议的中心假设也将在过敏性哮喘患者中进行探索。我们 一个小组研究了过敏性哮喘患者对支气管镜节段性变应原激发的反应， 哮喘（AA）和过敏性非哮喘对照（ANA）。我们发现气道2型细胞因子的产生增加， 与ANA受试者相比，AA中总粘蛋白和粘蛋白MUC 5AC对过敏原的反应。这些发现 提示气道内Th 2-Trm激活的差异可能对过敏原致敏的 个体发展为哮喘表型。我们将检验相对频率的差异， 肺中rTbR的表型和/或TCR特异性是对吸入性变应原反应差异的基础 ANA和AA受试者。具体而言，我们建议：（1）进一步明确肺rTbR在抑制肺纤维化中的作用， （2）确定CCR 8和CXCR 6趋化因子系统在组织驻留程序中的作用 rTbR在过敏性肺中的定位和功能;以及（3）通过比较 AA和ANA受试者中rT细胞的数量、表型和TCR特异性。