Project description:Patients with severe uncontrolled asthma represent a distinct endotype with persistent airway inflammation and remodeling refractory to corticosteroid treatment. CD4+ T cells and their canonical effector molecules, like type 2 cytokines, play a central role in orchestrating asthma pathogenesis, and biologic therapies targeting these 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. To address this issue in a hypothesis-free manner, we performed single-cell transcriptome analysis of >50,000 airway CD4+ T cells isolated from bronchoalveolar lavage (BAL) 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 (TRM) cells making a dominant contribution. Notably, a subset of CD4+ TRM 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. This subset was enriched for transcripts linked to T cell receptor (TCR) activation (HLA-DRB1, HLA-DPA1, CD40LG) and cytotoxicity (GZMB, GZMH), and following stimulation expressed high levels of transcripts encoding for pro-inflammatory non-TH2 cytokines (CCL3, CCL4, CCL5, TNF, IL-17A, CSF2, LIGHT) that could fuel persistent airway inflammation and remodeling. Furthermore, we found that CD4+ T cells isolated ex vivo from airways of severe asthmatics displayed signatures linked to corticosteroid resistance (FKBP5, DDIT4), as well as reduced expression of transcripts encoding for molecules that dampen TCR signaling and T cell effector functions (CREM, DUSP1, TNFAIP3). Overall, our single-cell transcriptomic analysis highlights the pathogenic properties and clinical associations of airway CD4+ T cell subsets in severe asthmatics, features that can potentially trigger their unrestrained activation, and that these findings were more pronounced in males. These pathways may therefore be crucial for driving disease severity in adult male severe asthmatics.

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Cytotoxic CD4+ tissue-resident memory T cells are associated with asthma severity

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