Neuropilin-1 is a receptor for transforming growth factor beta-1, activates its latent form, and promotes regulatory T cell activity

J Leukoc Biol. 2008 Jul;84(1):302-10. doi: 10.1189/jlb.0208090. Epub 2008 Apr 24.

Abstract

Neuropilin-1 (Nrp1) is a multifunctional protein, identified principally as a receptor for the class 3 semaphorins and members of the vascular endothelial growth factor (VEGF) family, but it is capable of other interactions. It is a marker of regulatory T cells (Tr), which often carry Nrp1 and latency-associated peptide (LAP)-TGF-beta1 (the latent form). The signaling TGF-beta1 receptors bind only active TGF-beta1, and we hypothesized that Nrp1 binds the latent form. Indeed, we found that Nrp1 is a high-affinity receptor for latent and active TGF-beta1. Free LAP, LAP-TGF-beta1, and active TGF-beta1 all competed with VEGF165 for binding to Nrp1. LAP has a basic, arginine-rich C-terminal motif similar to VEGF and peptides that bind to the b1 domain of Nrp1. A C-terminal LAP peptide (QSSRHRR) bound to Nrp1 and inhibited the binding of VEGF and LAP-TGF-beta1. We also analyzed the effects of Nrp1/LAP-TGF-beta1 coexpression on T cell function. Compared with Nrp1(-) cells, sorted Nrp1+ T cells had a much greater capacity to capture LAP-TGF-beta1. Sorted Nrp1(-) T cells captured soluble Nrp1-Fc, and this increased their ability to capture LAP-TGF-beta1. Conventional CD4+CD25(-)Nrp1(-) T cells coated with Nrp1-Fc/LAP-TGF-beta1 acquired strong Tr activity. Moreover, LAP-TGF-beta was activated by Nrp1-Fc and also by a peptide of the b2 domain of Nrp1 (RKFK; similar to a thrombospondin-1 peptide). Breast cancer cells, which express Nrp1, also captured and activated LAP-TGF-beta1 in a Nrp1-dependent manner. Thus, Nrp1 is a receptor for TGF-beta1, activates its latent form, and is relevant to Tr activity and tumor biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Female
  • Flow Cytometry
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Neuropilin-1 / metabolism*
  • Protein Isoforms / metabolism
  • Rats
  • T-Lymphocytes, Regulatory / immunology*
  • Transforming Growth Factor beta1 / metabolism*
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Protein Isoforms
  • Transforming Growth Factor beta1
  • Vascular Endothelial Growth Factor A
  • Neuropilin-1