La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton Foundation Trust, Southampton SO16 6YD, UK; The David Hide Asthma and Allergy Research Centre, St. Mary's Hospital, Newport PO30 5TG, Isle of Wight, UK.
Med. 2023 Dec 8;4(12):875-897.e8. doi: 10.1016/j.medj.2023.09.003. Epub 2023 Oct 20.
Patients with severe uncontrolled asthma represent a distinct endotype with persistent airway inflammation and remodeling that is refractory to corticosteroid treatment. CD4 T2 cells play a central role in orchestrating asthma pathogenesis, and biologic therapies targeting their cytokine pathways have had promising outcomes. However, not all patients respond well to such treatment, and their effects are not always durable nor reverse airway remodeling. This observation raises the possibility that other CD4 T cell subsets and their effector molecules may drive airway inflammation and remodeling.
We performed single-cell transcriptome analysis of >50,000 airway CD4 T cells isolated from bronchoalveolar lavage samples from 30 patients with mild and severe asthma.
We observed striking heterogeneity in the nature of CD4 T cells present in asthmatics' airways, with tissue-resident memory T (T) cells making a dominant contribution. Notably, in severe asthmatics, a subset of CD4 T cells (CD103-expressing) was significantly increased, comprising nearly 65% of all CD4 T cells in the airways of male patients with severe asthma when compared to mild asthma (13%). This subset was enriched for transcripts linked to T cell receptor activation (HLA-DRB1, HLA-DPA1) and cytotoxicity (GZMB, GZMA) and, following stimulation, expressed high levels of transcripts encoding for pro-inflammatory non-T2 cytokines (CCL3, CCL4, CCL5, TNF, LIGHT) that could fuel persistent airway inflammation and remodeling.
Our findings indicate the need to look beyond the traditional T2 model of severe asthma to better understand the heterogeneity of this disease.
This research was funded by the NIH.
严重未控制的哮喘患者代表了一种独特的表型，其持续存在气道炎症和重塑，对皮质类固醇治疗有抗性。CD4 T2 细胞在协调哮喘发病机制中发挥核心作用，靶向其细胞因子途径的生物疗法已取得可喜的结果。然而，并非所有患者对这种治疗反应良好，其效果并不总是持久的，也不能逆转气道重塑。这一观察结果提出了这样一种可能性，即其他 CD4 T 细胞亚群及其效应分子可能驱动气道炎症和重塑。
我们对 30 名轻度和重度哮喘患者支气管肺泡灌洗液中分离的 >50000 个气道 CD4 T 细胞进行了单细胞转录组分析。
我们观察到哮喘患者气道中存在的 CD4 T 细胞的性质存在显著的异质性，组织驻留记忆 T（T）细胞起主要作用。值得注意的是，在严重哮喘患者中，一种 CD4 T 细胞（表达 CD103）亚群显著增加，当与轻度哮喘相比时，严重哮喘男性患者气道中的所有 CD4 T 细胞中几乎占 65%（13%）。该亚群富含与 T 细胞受体激活（HLA-DRB1、HLA-DPA1）和细胞毒性（GZMB、GZMA）相关的转录本，并且在刺激后，表达高水平编码促炎非 T2 细胞因子（CCL3、CCL4、CCL5、TNF、LIGHT）的转录本，这些细胞因子可能引发持续的气道炎症和重塑。
我们的发现表明，需要超越严重哮喘的传统 T2 模型，以更好地理解这种疾病的异质性。
这项研究由 NIH 资助。
