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

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‐β1 (the latent form). The signaling TGF‐β1 receptors bind only active TGF‐β1, and we hypothesized that Nrp1 binds the latent form. Indeed, we found that Nrp1 is a high‐affinity receptor for latent and active TGF‐β1. Free LAP, LAP‐TGF‐β1, and active TGF‐β1 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‐β1. We also analyzed the effects of Nrp1/LAP‐TGF‐β1 coexpression on T cell function. Compared with Nrp1– cells, sorted Nrp1+ T cells had a much greater capacity to capture LAP‐TGF‐β1. Sorted Nrp1– T cells captured soluble Nrp1‐Fc, and this increased their ability to capture LAP‐TGF‐β1. Conventional CD4+CD25–Nrp1– T cells coated with Nrp1‐Fc/LAP‐TGF‐β1 acquired strong Tr activity. Moreover, LAP‐TGF‐β 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‐β1 in a Nrp1‐dependent manner. Thus, Nrp1 is a receptor for TGF‐β1, activates its latent form, and is relevant to Tr activity and tumor biology.