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

Mojdeh Matloubi1, Chukwunonso Onyilagha1, Lianyu Shan1

  • 1Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|July 20, 2026
PubMed

Insights

Semaphorin3E (Sema3E) from airway epithelial cells promotes regulatory T (Treg) cell function. Disrupting the Sema3E-plexinD1 pathway in Treg cells exacerbates asthma symptoms, highlighting its therapeutic potential.

Area of Science:

  • Immunology
  • Pulmonology
  • Cell Biology

Background:

  • Airway epithelial cells (AECs) produce Semaphorin3E (Sema3E), crucial for lung homeostasis.
  • Sema3E expression is reduced in severe asthma, indicating its protective role.
  • The function of AEC-derived Sema3E in asthma pathogenesis remains unclear.

Purpose of the Study:

  • To investigate the impact of AEC-derived Sema3E on immune responses in a house dust mite (HDM)-induced asthma model.
  • To elucidate the role of the Sema3E-plexinD1 signaling pathway in regulatory T (Treg) cells during asthma.

Main Methods:

  • Generated transgenic mice with tamoxifen-inducible Sema3E overexpression in AECs.
  • Created cell-specific Foxp3-PLXND1 knockout (KO) mice to assess Sema3E-plexinD1 signaling in Treg cells.
  • Exposed mice to HDM to induce an acute asthma model and analyzed immune cell populations, cytokine levels, and airway hyperresponsiveness.

Main Results:

  • Sema3E overexpression in AECs increased lung Treg cell number and proliferation but did not affect other immune cells or BALF cytokines.
  • Foxp3-PLXND1 KO mice showed reduced Treg cells, increased lung eosinophils, elevated IFN-γ+ CD4+ T cells, and higher BALF IL-17, IL-5, and CXCL8 levels.
  • Deficiency in Foxp3-PLXND1 signaling also enhanced T follicular helper cells, germinal center B cells, IgG1/IgE antibodies, Muc5AC expression, and goblet cell hyperplasia.

Conclusions:

  • The Sema3E-plexinD1 axis is a critical regulator of Treg cell-mediated immune homeostasis in the lungs.
  • Disruption of this axis impairs Treg function, leading to exacerbated allergic airway inflammation and asthma-like pathology.
  • Targeting the Sema3E-plexinD1 pathway represents a potential therapeutic strategy for asthma.
Keywords:
PlexinD1Semaphorin3Eairway epithelial cellsairway hyperresponsivenessairway inflammationairway remodelingasthmaregulatory T cell

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