# Neuropilin-2 in Alloimmunity

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $509,048

## Abstract

Project Summary/Abstract
Allograft rejection is characterized by effector CD4+ T cell activation in response to donor antigen and an
intense cellular and humoral attack on the graft. However, multiple intracellular signals within CD4+ T cells
operate co-incidentally to control and regulate effector alloimmunity, and it is proposed that this process of
immunoregulation is a vital and perhaps more potent component of the response. The neuropilin (NRP)
receptors, NRP-1 and NRP-2, are single spanning transmembrane glycoproteins that were initially
discovered as chemorepulsive mediators of axonal guidance. However, they are now recognized to function
in a wide range of important biological processes including migration, angiogenesis, and cell growth. In
addition, they have recently been shown to have pluripotent functions in the immune response as well as in
tumor initiation and progression. Over the past decade, several groups have identified critical functions for
NRP-1 in immunity, notably related to its expression on induced Tregulatory cells where it functions to
augment immunoregulation. In contrast, much less is known about the immunological function of NRP-2
and it has only recently been demonstrated to be expressed on immune cells. In preliminary studies, we find
that NRP-2 is expressed on subsets of both human and murine CD4+ effector and regulatory cells.
Furthermore, we find that Semaphorin3F, a well established ligand for NRP-2, is potent to inhibit PI-3K
activity as well as mTOR signaling that are reported to modulate CD4+ T cell activation. Also, we find that
CD4+ T cells from NRP-2 knockout mice mount enhanced effector responses following activation in vitro
and in vivo. These observations have shaped a working model whereby the induced expression of NRP-2
on CD4+ T cells functions to modulate activation, and they suggest that its biological effects have
consequences for the outcome of the alloimmune response. Our objectives in this R01 are to: 1), identify
how NRP-2 modulates regulatory signaling responses and cell metabolism in CD4+ subsets, 2), evaluate
whether Semaphorin3F serves to regulate CD4+ T cell activation responses, and 3), evaluate whether
Sema3F-NRP-2 interactions can be exploited in vivo to augment immunoregulation post transplantation
and/or to induce Teffector responses that limit cancer growth. We will test the hypothesis that CD4+ T cell
NRP-2 interacts with Semaphorin3F and/or additional ligands to modulate Teffector cell activation and to
augment Tregulatory cell function and immunoregulation following transplantation. We propose two specific
aims in which we will: 1), identify the mechanism of NRP-2-induced regulatory signaling and the
consequences of NRP-2 loss in CD4+ T cell subsets, and 2), determine the function of CD4+ T cell NRP-2 in
the prevention of rejection and in long-term allograft survival. Collectively, these innovative studies will have
broad scientific and biological implications of great signific...

## Key facts

- **NIH application ID:** 10114967
- **Project number:** 5R01AI148539-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** David M. Briscoe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $509,048
- **Award type:** 5
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114967

## Citation

> US National Institutes of Health, RePORTER application 10114967, Neuropilin-2 in Alloimmunity (5R01AI148539-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10114967. Licensed CC0.

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