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，其患病率仍在上升，约占全球人口的8%