Pro-lymphangiogenic VEGFR-3 signaling modulates memory T cell responses in allergic airway inflammation

Mucosal Immunol. 2021 Jan;14(1):144-151. doi: 10.1038/s41385-020-0308-4. Epub 2020 Jun 9.


In allergic airway inflammation, VEGFR-3-mediated lymphangiogenesis occurs in humans and mouse models, yet its immunological roles, particularly in adaptive immunity, are poorly understood. Here, we explored how pro-lymphangiogenic signaling affects the allergic response to house dust mite (HDM). In the acute inflammatory phase, the lungs of mice treated with blocking antibodies against VEGFR-3 (mF4-31C1) displayed less inflammation overall, with dramatically reduced innate and T-cell numbers and reduced inflammatory chemokine levels. However, when inflammation was allowed to resolve and memory recall was induced 2 months later, mice treated with mF4-31C1 as well as VEGF-C/-D knockout models showed exacerbated type 2 memory response to HDM, with increased Th2 cells, eosinophils, type 2 chemokines, and pathological inflammation scores. This was associated with lower CCL21 and decreased TRegs in the lymph nodes. Together, our data imply that VEGFR-3 activation in allergic airways helps to both initiate the acute inflammatory response and regulate the adaptive (memory) response, possibly in part by shifting the TReg/Th2 balance. This introduces new immunomodulatory roles for pro-lymphangiogenic VEGFR-3 signaling in allergic airway inflammation and suggests that airway lymphatics may be a novel target for treating allergic responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allergens
  • Animals
  • Biomarkers
  • Disease Susceptibility
  • Immunologic Memory*
  • Immunophenotyping
  • Lymphangiogenesis* / genetics
  • Mice
  • Pyroglyphidae / immunology
  • Respiratory Hypersensitivity / etiology*
  • Respiratory Hypersensitivity / metabolism*
  • Respiratory Hypersensitivity / pathology
  • Signal Transduction*
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism*
  • Vascular Endothelial Growth Factor C / genetics
  • Vascular Endothelial Growth Factor C / metabolism
  • Vascular Endothelial Growth Factor Receptor-3 / genetics
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism*


  • Allergens
  • Biomarkers
  • Vascular Endothelial Growth Factor C
  • vascular endothelial growth factor C, mouse
  • Vascular Endothelial Growth Factor Receptor-3