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

基本信息

批准号：
10563192
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
项目类别：
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/10563192
关键词：
Adoptive Transfer Allergens Allergic Allergic inflammation Anatomy Antigens Asthma Bone Marrow CCL1 gene CCL8 gene CCR8 gene CD4 Positive T Lymphocytes CXCR CXCR6 gene Cell Proliferation Cell Separation 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 Ligands Location Lung MUC5AC gene Maintenance Mediating Memory Metaplasia Modeling Mucins Mucous body substance Mus Pattern Peptides Phenotype Play Population Positioning Attribute Prevalence Production Pulmonary Inflammation Pyroglyphidae Regulatory T-Lymphocyte Reporter Residencies Resolution Role Specificity Surface System T cell differentiation T memory cell Testing Th2 Cells Therapeutic Time Tissues Transgenic Mice Up-Regulation airborne allergen airway hyperresponsiveness airway immune response airway inflammation allergic response asthma model chemokine chemokine receptor chronic inflammatory disease cost estimate cytokine efficacy evaluation environmental allergen eosinophil experimental study novel therapeutic intervention programs response single-cell RNA sequencing transcriptome sequencing

项目摘要

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，其患病率仍在上升，约占全球人口的 8% 美国人口和估计每年 820 亿美元的成本。需要新的治疗方法来提供长期治愈的潜力。过敏性哮喘是最常见的内型，被认为是由很大程度上是由于对吸入过敏原的 2 型气道免疫反应。 Foxp3+ 调节性 T 细胞 (Treg) 非常有效免疫反应的抑制剂，是治疗过敏性哮喘的一个有吸引力的目标。 CD4+ T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器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驻留在肺中的常驻记忆 (Trm) Th2 细胞是驱动许多功能的关键效应细胞过敏性哮喘的特点。 Th2-Trm 细胞在过敏原挑战后在气道附近增殖，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。尽管记忆 T 细胞被认为会在宿主体内不断地再循环，最近已经清楚 Trm 保持解剖学定位，以在屏障表面启动抗原特异性免疫反应。在初步研究，我们现在发现过敏原特异性Tregs也存在于空气过敏原之后的肺部敏化，是抑制 Th2-Trm 反应的关键细胞。这把我们引向了中央该提议的假设是，Th2-Trm 的常驻 (r) Treg 抑制是调节过敏性哮喘的关键表型。 Th2-Trm 表现出独特的转录程序，包括趋化因子的上调受体 CCR8 和 CXCR6。在初步研究中，我们发现肺部的rTregs也上调CCR8 和 CXCR6 在 2 型反应期间。这使我们推测 CCR8 和 CXCR6 趋化因子系统在 Tregs 的组织驻留计划中发挥作用，并且能够与 Th2-Trm 并列航空公司。该提案的中心假设也将在患有过敏性哮喘的人类中进行探索。我们的研究小组研究了过敏症患者对支气管镜节段性过敏原激发的反应哮喘（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 受试者对过敏原的总粘蛋白和粘蛋白 MUC5AC 的反应。这些发现表明气道内 Th2-Trm 激活的差异可能对于过敏原敏感的患者至关重要个体发展出哮喘表型。我们将检验相对频率差异的假设，肺部 rTreg 的表型和/或 TCR 特异性是对空气过敏原反应差异的基础 ANA 和 AA 科目。具体来说，我们建议：（1）进一步明确肺rTregs在抑制 Th2-Trm； (2) 确定CCR8和CXCR6趋化因子系统在组织住院医师计划中的作用 rTregs 在过敏性肺中的定位和功能； (3) 通过比较将这些研究扩展到人类 AA 和 ANA 受试者中 rTreg 的数量、表型和 TCR 特异性。