T cell-specific Themis deletion attenuates allergic airway inflammation by suppressing Th2–ILC2-associated responses in an ovalbumin-induced asthma model

Asthma is characterized by airway hyperresponsiveness, type 2 inflammation, and mucus-associated airway remodeling. Themis is a T cell-specific signaling regulator involved in T-cell development and effector function, but its role in allergic airway inflammation remains unclear. This study investigated whether T cell-specific Themis deletion affects ovalbumin (OVA)-induced acute allergic airway inflammation and explored the associated immune mechanisms. An acute allergic airway inflammation model was established in wild-type (WT) and T cell-specific Themis conditional knockout (cKO) mice using OVA/alum sensitization followed by aerosolized OVA challenge. Airway hyperresponsiveness, bronchoalveolar lavage fluid (BALF) inflammatory cell infiltration, serum IgE/IgG1 levels, BALF type 2 cytokines, and lung histopathology were assessed. Flow cytometry was used to analyze Th2 cytokine-producing CD4⁺ T cells in the lung and mediastinal lymph nodes, as well as pulmonary ILC2 accumulation and effector phenotypes. Lung ST2 and phosphorylated STAT6 (p-STAT6) signals were evaluated by immunofluorescence. OVA-challenged WT mice developed typical asthmatic features, including increased airway hyperresponsiveness, BALF inflammatory cell infiltration, pulmonary inflammation, mucus hypersecretion, elevated serum IgE/IgG1, and increased BALF IL-4, IL-5, and IL-13 levels. Compared with WT-OVA mice, Themis cKO-OVA mice showed reduced airway hyperresponsiveness, decreased BALF eosinophil accumulation, lower lung inflammation and mucus scores, reduced serum IgE, and decreased BALF type 2 cytokines. Themis deficiency also reduced IL-4-, IL-5-, and IL-13-producing CD4⁺ T cells in both the lung and mediastinal lymph nodes. Pulmonary ILC2 accumulation was limited in cKO mice, accompanied by partial reduction of cytokine-producing ILC2 subsets. In addition, ST2 and p-STAT6 signals were diminished in lung tissue from cKO-OVA mice. T cell-specific deletion of Themis attenuates OVA-induced allergic airway inflammation by suppressing Th2 responses, limiting pulmonary ILC2 accumulation, and reducing ST2–STAT6-associated type 2 inflammatory signaling.