Sema3E ‐ plexinD1 Axis Is a Modulator of Foxp3 ⁺ Regulatory T‐Cells in House Dust Mite Model of Asthma

Airway epithelial cells (AEC) are the primary sources of Semaphorin3E (Sema3E) in human airways and its expression is downregulated in severe asthmatics, underscoring the AEC‐derived Sema3E critical role in lung homeostasis. Here, we investigated the effects of AEC‐derived Sema3E on immune responses in an acute house dust mite (HDM) asthma model. Transgenic Sema3E overexpression in AECs, using tamoxifen‐inducible Scgb1a1Cre, did not alter lung neutrophils, eosinophils, macrophages, dendritic cells, B cells, and CD4 T‐cell number and BALF cytokine levels. However, it significantly increased lung Foxp3 + Treg cell number and proliferation. To assess the role of Sema3E‐plexinD1 signaling in Foxp‐3 cells, cell‐specific Foxp3‐PLXND1 knockout (KO) mice were subjected to HDM exposure. These mice exhibited reduced Foxp3 + Treg cell numbers in the lungs, spleen, and mediastinal lymph nodes, accompanied by increased lung eosinophil infiltration, elevated IFN‐γ + CD4 + T cells in the spleen, and higher BALF levels of IL‐17, IL‐5, and CXCL8. Foxp3 PLXND1 deficiency also enhanced the number of T follicular helper cells, germinal center B cells, and IgG1/IgE antibodies in sera. Additionally, Muc5AC gene expression and goblet cell hyperplasia were elevated in Foxp3 PLXND1 KO mice. These findings highlight the Sema3E‐plexinD1 axis as a key regulator of Treg cell‐mediated immune homeostasis, suggesting its therapeutic potential in asthma.