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Original Research Open Access

VEGF-D Dependent IFNγ Production by Natural Killer Cells in Lymphangioleiomyomatosis

  • 1University of Cincinnati College of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, PO Box 45267-0564, Cincinnati, OH 45267
  • 2Oregon Health & Science University, Portland, Multnomah County, Oregon, United States
  • 3University of Cincinnati College of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, PO Box 45267-0564, Cincinnati, OH 45267
  • 4University of Cincinnati College of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, PO Box 45267-0564, Cincinnati, OH 45267
  • 5University of Cincinnati College of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, PO Box 45267-0564, Cincinnati, OH 45267
  • 6University of Cincinnati College of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, PO Box 45267-0564, Cincinnati, OH 45267
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Corresponding Author

Michael Borchers, Michael.borchers@uc.edu

Received Date: November 04, 2025

Accepted Date: December 22, 2025

Abstract

Lymphangioleiomyomatosis (LAM) is a rare cystic neoplasm that almost exclusively affects women. LAM arises from inherited or spontaneous mutations in TSC1 or TSC2 genes, which result in constitutive activation of mTOR and downstream signaling. These mutations arise in a uterine population of cells that migrate to the lungs where they establish nodules that progress to cysts and progressive lung function decline. Clinically, an elevated level (>800 pg/ml) of vascular endothelial growth factor -D (VEGF-D) is a definitive diagnostic marker for LAM. Recent work by our group and others highlights the role of immune dysfunction in the establishment and progression of LAM. A subset of natural killer (NK) cells in LAM express the VEGF-D receptors, VEGFR3 and NRP2. These distinct NK cells are responsive to VEGF-D treatment and LAM NK cells have altered NKG2D and CD160 expression, as well as changes in phosphorylation of STAT4(Y693) and ERK1/2 (Y202/S204). Phosphorylation of these proteins increases after VEGF-D treatment at short time points (0-30 min) and longer time points (up to 6 hours). In addition, the signaling kinetics are altered compared to cytokine stimulation. Increased IFNγ production was shown by ELISA and flow cytometry after VEGF-D, and other cytokines. Baseline IFNγ expression is higher in LAM NK cells, and LAM NK cells elaborate IFNγ when stimulated with VEGF-D. Additionally, these NK cells have increased responsiveness to IL12/33 and decreased responsiveness to IL12/IL27 co-stimulation. These data demonstrate that NK cells from LAM patients are functionally altered and these changes in baseline function may contribute to disease progression and pathology.

Keywords

Natural Killer cells, Phosphorylation, VEGFR3, Lymphangioleiomyomatosis, Cytokines, IFNγ, pSTAT4, pERK1/2

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