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Published online before print April 24, 2008

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(Journal of Leukocyte Biology. 2008;84:302-310.)
© 2008 by Society for Leukocyte Biology

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

Department of Laboratory Medicine, St. Michael’s Hospital and University of Toronto, Ontario, Canada

¹Correspondence: Department of Laboratory Medicine, St. Michael’s Hospital, 30 Bond Street, Room 2-013CC, Toronto, Ontario, Canada M5B 1W8. E-mail: glinkay{at}smh.toronto.on.ca

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.

Key Words: binding motif • VEGF • LAP-TGF-β1 • signal transduction • CD4⁺CD25^– • T lymphocytes • suppressor cells

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