NRP1 in Effector and Regulatory CD4+ T Cell Populations.

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Background: Neuropilins (NRP1 and NRP2) serve as receptors for class 3 family semaphorins and were originally described as axonal guidance molecules. More recently, NRP1 has been found to be highly expressed on most CD4+Foxp3+ regulatory T cells (Treg) and to facilitate DC-Treg interactions and the migration of Treg into tumors and inflammatory sites. NRP1 forms a complex with plexin family molecules that function in T cell activation. However, little is known about NRP1 ligands, and so far no study has addressed its function in the context of transplantation. Methods and Results: 1) CD4+ T cells from wild type B6 mouse spleen, thymus and peripheral lymph nodes were FACS stained for neuropilins and Treg specific markers. NRP1 was found on over 80% of all CD4+Foxp3+ Treg and its expression significantly correlated with the expression of CD25, CTLA-4, GITR, Helios and OX40 on the same cells; CD4+Foxp3- conventional T cells expressed NRP1 at low levels of around 10%. NRP2 and VEGFR1 were variably expressed by about 2-20% of Treg and Tconv. 2) Naïve Tconv were stimulated in vitro with anti-CD3/CD28 or APC. CD25 was upregulated on all Tconv within 24 hours, NRP1 levels however remained fairly stable at 10-20% over a 96-hr time course. 3) CD4+CD25- Tconv were magnetically separated and cultured in vitro under Treg inducing conditions for 5 days. Resulting CD4+Foxp3+CD25+ iTreg were found to express NRP1 at high levels over 80%. 4) To test whether Sema3A has potential to alter activation responses, we used a NRP1-expressing cell line (U87MG) and evaluated the effect of Sema3A on cell signaling responses. By western blot analysis, there was a time dependent strong inhibition of Akt phosphorylation. NRP1/plexin receptor complexes are the only known transmitters of Sema3A signaling to date. Conclusions: The expression of NRP1 on CD4+Foxp3+ T cells correlates very well with other proteins that are characteristic for Tregs and confirms NRP1 as a Treg specific marker. Unlike CD25 however, NRP1 is not upregulated on CD4+ effector T cells. Also, despite controversial reports from earlier studies, we find that NRP1 is strongly expressed on induced Tregs. Hence, NRP1 is a surface molecule that reliably distinguishes Treg from effector T cells. Sema3A-mediated inhibition of PI3K-Akt/mTOR signaling in NRP1-expressing cells suggests an extensive functional role for NRP1 in regulatory immune responses. DISCLOSURES:Briscoe, D.: Grant/Research Support, Pfizer.

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