Emerging Role and Function of Th9 Cells in Allergic Inflammation

Kaminuma O, Kitamura N, Gotoh M.  J Inflamm Res. 2025 Nov 22;18:16385-16397. doi: 10.2147/JIR.S546234.

Abstract: 

Th9 cells have emerged as pivotal orchestrators of allergic inflammation across the airway, skin, and nasal mucosa, constituting a mechanistically distinct axis beyond canonical Th2 immunity. This review specifically highlights: (i) the Th9 axis as a unifying driver in asthma, atopic dermatitis, and allergic rhinitis; (ii) key mechanistic programs, including signal transducer and activator of transcription (STAT) 5/STAT6 licensing of the IL9 locus, peroxisome proliferator-activated receptor (PPAR) γ-mammalian target of rapamycin complex (mTORC) 1 metabolic wiring, and the IL-9-monocarboxylate transporter (MCT) 1 feedback loop; (iii) organ-level phenotypes such as eosinophil-independent bronchial hyperresponsiveness (BHR) and variable steroid responsiveness; and (iv) therapeutic implications, including biomarker-guided endotyping, Janus kinase (JAK) inhibition, TNF-like ligand (TL) 1A/death receptor (DR) 3 blockade, and metabolic or airway smooth muscle (ASM) tone modulation. Differentiating under the combined influence of interleukin (IL)‑4 and tumor growth factor (TGF)-β, Th9 cells secrete IL‑9, a pleiotropic cytokine that drives mast‑cell proliferation, goblet cell metaplasia, and airway remodeling. Their transcriptional program is epigenetically licensed by STAT5/STAT6, which opens chromatin at the IL9 locus and is metabolically sustained by a PPARγ-mechanistic/mTORC1-dependent glycolytic state. This bioenergetic wiring establishes an IL‑9-MCT1 feedback loop that reinforces effector function and durability. 

Th9 Axis Across Allergic Diseases: Pathobiology,
Biomarkers, and Therapeutic Implications

Clinically, Th9 signatures align with BHR, which can be eosinophil-independent and variably responsive to inhaled corticosteroids; experimental models further demonstrate that Th9‑mediated BHR persists in eosinophil-deficient contexts and displays relative glucocorticoid resistance.

Within the broader landscape of bronchial asthma, a chronic inflammatory disease marked by reversible airway obstruction, mucus hypersecretion, and BHR, these insights help explain the non‑Th2 endotypes that respond poorly to standard anti-inflammatory therapies. Although anti-IL‑9 monoclonal antibodies have not improved lung function in unselected asthma cohorts, aggregate evidence argues for biomarker‑guided endotyping and upstream pathway intervention, including tumor necrosis factor-like cytokine TL1A/DR3 blockade and metabolic modulation, as more rational strategies to disrupt Th9 pathogenic circuits. Importantly, the Th9 axis also represents one of the non-IgE‑mediated hypersensitivity mechanisms pertinent to allergic conditions, a perspective that enhances clinical discoverability and bench‑to‑bedside translation. This review integrates foundational mechanistic and pharmacologic knowledge with recent advances, positioning Th9 cells as a unifying driver across asthma, atopic dermatitis, and allergic rhinitis, and delineates therapeutic avenues that target epigenetic, metabolic, and cytokine networks sustaining Th9‑dependent diseases.

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