Semin Immunol. 2026 Feb 24;81:102017. doi: 10.1016/j.smim.2026.102017. Online ahead of print.
ABSTRACT
Upon antigenic stimulation and cytokine cues, CD4⁺ T cells differentiate into specialized helper subsets, giving rise to Th1, Th2, Th9 and Th17 cell lineages. These subsets orchestrate distinct immune functions that protect the host but can also drive immunopathology when dysregulated. The classical Th1-Th2 paradigm expanded with the discovery of Th17 and Th9 cells, revealing greater diversity and complexity in Th cell biology. Th9 cells, generated under the influence of TGF-β and IL-4, are defined by robust production of interleukin-9 (IL-9). IL-9 is now recognized as a multifunctional mediator produced by Th9 cells, mast cells, ILC2s, Tregs and certain Th17 subsets. Fate-mapping and reporter mouse models have improved our understanding of IL-9-producing immunocytes, though limitations remain in defining temporal and tissue-specific dynamics. As shown earlier, IL-9 promotes mastcell proliferation, mucus hypersecretion, epithelial changes and airway remodelling in allergic inflammation and asthma. Genetic studies have linked IL-9/IL-9 receptor variants to increased susceptibility to allergic diseases such as asthma. Similarly, during respiratory viral infections, including RSV and COVID-19, IL-9 amplifies type 2 inflammation, granulocyte recruitment and mucus production, exacerbating airway obstruction. In fact, emerging evidence implicates a Foxo1-IL-9 axis in COVID-19, where IL-9 enhances lung inflammation and impairs antiviral interferon-stimulated gene responses. Collectively, IL-9 represents a context-dependent driver of virus-induced lung pathology and a promising therapeutic target requiring deeper mechanistic and translational investigation.
PMID:41740281 | DOI:10.1016/j.smim.2026.102017