NRP-1 and IL-17–producing NKT cells

NRP-1 is a neuronal surface receptor involved in axon guidance. In the past few years, it has also been implicated in dendritic cell–T cell interactions. In this issue of Blood, Milpied et al find that NRP-1 is a marker of recently generated IL-17–producing natural killer (NK) T cells.¹ 

Neuropilin-1 (NRP-1) is a transmembrane glycoprotein and was first described as a neuronal surface receptor involved in axon guidance.²  It functions by binding semaphorins, a family of chemorepulsive molecules.³  However, the role of NRP-1 extends outside the nervous system, and many of the functions have yet to be defined. NRP-1 is a vascular receptor expressed on endothelial cells and was found to bind selectively to the 165 amino acid form of VEGF (VEGF165).⁴  The neuropilins also interact directly with the classic receptors for VEGF, VEGF-R1 and -R2, and function as co-receptors by mediating signal transduction.^4,5  Their role in angiogenesis has been shown both in physiologic and pathologic situations.⁵  Manipulating neuropilin function can regulate tumor growth and metastasis through effects on vascular biology in the case of neuropilin-1, and lymphatic biology in the case of neuropilin-2.⁶  More recently, NRP-1 was shown to be a part of the HTLV-1 receptor complex.⁷ 

The involvement of NRP-1 in the immune system was first shown in 2002 in the immune synapse.⁸  NRP-1 expression on activated T cells and dendritic cells (DCs) mediates homotypic interactions promoting the initiation of the primary immune response.⁸  Parallel studies showed that semaphorins are important molecules in the cross-talk between T cells and DCs.⁹  Since then, our knowledge of NRP-1 function in the immune system has progressed slowly. NRP-1 was shown to be expressed on plasmacytoid predendritic cells (pDCs).¹⁰  Recent work has shown that mouse regulatory T cells (Tregs) express NRP-1, which enhances their interaction with DCs and subsequently favors a tolerogenic response to low-dose antigens in the absence of danger signals.¹¹  However, human Tregs were not found to express NRP-1.¹²  .pDCs are the only cell type expressing NRP-1 in the steady state in human blood and secondary lymphoid tissue.¹⁰  However, semaphorins may promote regulatory responses by binding NRP-1 on activated T cells and participate in the termination of the immune synapse through their chemorepulsive action.¹³  Hence, major questions remain regarding the expression profile of NRP-1 on immune cells in humans and mice, as well as the functions of NRP-1 in vivo and in vitro.

Milpied et al found that NRP-1 was expressed on recent thymic NKT cell emigrants, but not long-lived mature NKT cells.¹  Using NRP-1 as a biomarker, they were able for the first time to comparatively study the function and cytokine production of these 2 NKT cell populations. They could show that recent thymic emigrant NKT cells predominantly produced IL-17, but not IFN-g and IL-4, a classic feature of mature NKT cells. This suggested that a continuous thymic output is required for in vivo IL-17 production by recent thymic emigrant NKT cells. Equally important, this study identifies a novel biomarker for IL-17–producing NKT cells and extends the expression pattern of NRP-1 to NKT cells.

The work by Milpied et al raises many important questions. In terms of NKT cell biology, why is IL-17 production restricted to recent thymic emigrants and lost on mature NKT cells? Does it constitute a regulatory mechanism to avoid excessive proinflammatory IL-17 production? In terms of NRP-1 biology, what is the function of NRP-1 on these recent thymic emigrant NKT cells? What is the nature of putative endogenous ligands for NRP-1 in the thymus? NRP-1 can function through both homotypic and heterotypic ligand-receptor interactions. Thus, NRP-1–expressing NKT cells may interact with other NRP-1–expressing cells, including NKT and T cells, as well as DCs. Alternatively, NRP-1 may bind to other known ligands, such as VEGF. TGF-b is also an interesting candidate, because it is produced in the thymus and NRP-1 can function as a TGF-b co-receptor.

In summary, the identification of NRP-1 as a novel biomarker for IL-17–producing NKT cells will enable the purification of this cell population, and will certainly speed up its functional characterization. The function of NRP-1 on NKT cells remains a major question. It will be important to pursue the study of NRP-1 biology in a systematic manner, in both humans and mice, taking into account the various possible ligands as well as species-related differences, to solve the many remaining mysteries around this multifaceted molecule.