Introduction: Neuropilin-1 (NRP1) is a co-receptor for a variety of ligand families including VEGF, EGF and semaphorins all of which are often produced by malignant tumors and during tissue injury. NRP1 is highly expressed on CD4+ regulatory T cells (Treg) and has been reported to be critical for the migration, stabilization and suppressive function of these cells. The role of NRP1 for Treg and other immune cells has so far been primarily studied in the context of cancer with only a few studies to date looking at its role in transplantation. We present an overview of NRP1 expression on regulatory (Treg) and conventional (Tconv) CD4+ T cells and on CD8+ T cells in the naive state as well as under activation in vivo and in vitro.

Methods and Results: 1) FACS stainings were performed to investigate the expression of NRP1 in peripheral and central immune organs in naive C57BL/6 mice. In the periphery, NRP1 was found at high levels on the surface of 75-95% of all CD4+ Treg, but in only 5-10% of CD4+ Tconv and 1-5% of CD8+ T cells. In the thymus, NRP1 expression on CD4+ Treg and Tconv was similar to the periphery but significantly higher on single positive CD8+ T cells (20-40%). No significant differences were found based on the age of the mice (3-4 weeks, 8-12 weeks and 25-28 weeks). 2) After in vitro stimulation of splenocytes for up to four days, NRP1 was downregulated on CD4+ Treg as far as 60-65% and slightly upregulated on CD4+ Tconv up to 20%, but significantly increased to about 60% on CD8+ T cells. CD25, in contrast, was uniformly upregulated and expressed on all CD4+ and CD8+ T cells. 3) For in vivo activation of T cells, mice were transplanted with syngeneic B6 or fully MHC mismatched Balb/c skins and sacrificed about 8-10 days later to analyze NRP1 expression during graft rejection. T cells from draining lymph nodes of animals that rejected grafts displayed NRP1 downregulation on Treg and an upregulation on CD8+ T effectors and thus showed expression patterns similar to those seen upon in vitro activation.

Conclusions: In vitro stimulation and allogeneic in vivo stimulation changes expression levels of NRP1 on T cell subsets, suggesting a possible role for this molecule in transplantation rejection. Additional studies are ongoing to examine the role of NRP1 on Treg function as well as CD8+ T cell cytotoxicity.

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