Yang Zuqin, Krammer Susanne, Mitländer Hannah, Grund Janina C, Zirlik Sabine, Wirtz Stefan, Rauh Manfred, Shermeh Atefeh Sadeghi, Finotto Susetta
Department of Molecular Pneumology, Friedrich-Alexander-University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.
Department of Internal Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.
J Allergy Clin Immunol Glob. 2024 Oct 18;4(1):100355. doi: 10.1016/j.jacig.2024.100355. eCollection 2025 Feb.
Asthma, a chronic lung disease, is a significant public health problem worldwide. It is marked by increased T2 response resulting in eosinophil accumulation. The pathophysiology of asthma involves various cell types, including epithelial cells, dendritic cells (DCs), innate lymphoid cells, B cells, and effector cells. Nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), a critical transcription factor for immune regulation, is known for its role in T cells and, more recently, in myeloid cells. However, the specific contributions of NFATc1 in T cells and DCs in the context of asthma are not well understood.
We explored NFATc1's role in T cells and DCs in modulating T2 immune responses within the pathophysiology of allergic asthma.
We induced asthma in mice lacking in CD4 T cells or CD11c DCs using house dust mite, thereby enabling investigation into NFATc1's role in both cell types in experimental allergic asthma. Additionally, we examined NFATc1 expression in these cell types and its correlation with blood eosinophil levels in an adult asthma cohort.
In a house dust mite-induced asthma model, we found that deficiency either in CD4 T cells or CD11c DCs resulted in reduced T2-driven eosinophilic inflammation, IgE levels, and mast cell presence in the lung of asthmatic mice. 's absence in CD4 T cells directly hampered T2 cell polarization and functionality, whereas in CD11c DCs, it affected DC differentiation and maturation, thereby weakening T-cell priming, proliferation, and subsequent T2 differentiation. Correspondingly, translational research indicated significant correlations between CD4NFATc1 and CD11cNFATc1 cell populations and eosinophil levels in asthmatic patients, but not in healthy controls.
NFATc1 in T cells and DCs modulates T2-mediated eosinophilic inflammation in allergic asthma, thus offering insight into asthma pathogenesis and identifying NFATc1 as a potential target for therapeutic intervention.
哮喘是一种慢性肺部疾病，是全球范围内一个重大的公共卫生问题。其特征是T2反应增强，导致嗜酸性粒细胞积聚。哮喘的病理生理学涉及多种细胞类型，包括上皮细胞、树突状细胞（DCs）、固有淋巴细胞、B细胞和效应细胞。活化T细胞核因子细胞质1（NFATc1）是免疫调节的关键转录因子，以其在T细胞中的作用而闻名，最近也发现其在髓样细胞中发挥作用。然而，在哮喘背景下，NFATc1在T细胞和DCs中的具体作用尚未完全明确。
我们探讨了NFATc1在T细胞和DCs中对过敏性哮喘病理生理学中T2免疫反应的调节作用。
我们使用屋尘螨诱导缺乏CD4 T细胞或CD11c DCs的小鼠患哮喘，从而能够研究NFATc1在实验性过敏性哮喘的这两种细胞类型中的作用。此外，我们检测了这些细胞类型中NFATc1的表达及其与成年哮喘队列中血液嗜酸性粒细胞水平的相关性。
在屋尘螨诱导的哮喘模型中，我们发现CD4 T细胞或CD11c DCs的缺失导致哮喘小鼠肺部T2驱动的嗜酸性粒细胞炎症、IgE水平和肥大细胞数量减少。CD4 T细胞中NFATc1的缺失直接阻碍了T2细胞极化和功能，而在CD11c DCs中，它影响了DC的分化和成熟，从而削弱了T细胞的致敏、增殖及随后的T2分化。相应地，转化研究表明哮喘患者中CD4NFATc1和CD11cNFATc1细胞群体与嗜酸性粒细胞水平之间存在显著相关性，但在健康对照中则无此相关性。
T细胞和DCs中的NFATc1调节过敏性哮喘中T2介导的嗜酸性粒细胞炎症，从而为哮喘发病机制提供了见解，并确定NFATc1为治疗干预的潜在靶点。
