The initiation of a primary immune response requires contact between dendritic cells (DCs) and resting T cells. However, little is known about the proteins that mediate this initial contact. We show here that neuropilin-1, a receptor involved in axon guidance, was expressed by human DCs and resting T cells both in vitro and in vivo. The initial contact between DCs and resting T cells led to neuropilin-1 polarization on T cells. DCs and resting T cells specifically bound soluble neuropilin-1, and resting T cells formed clusters with neuropilin-1-transfected COS-7 cells in a neuropilin-1-dependent manner. Functionally, preincubation of DCs or resting T cells with blocking neuropilin-1 antibodies inhibited DC-induced proliferation of resting T cells. These data suggest that neuropilin-1 mediates interactions between DCs and T cells that are essential for initiation of the primary immune response and show parallels between the nervous and immune systems.

IntroductionErythropoiesis is a multistep process involving the differentiation of pluripotent hematopoietic stem cells through the lineagecommitted burst-forming unit-erythroid (BFU-E) and colonyforming unit-erythroid (CFU-E) progenitor cells. These progenitors give rise to a series of early and late erythroblasts, leading to the formation of reticulocytes and finally mature erythrocytes. 1 Interactions between hematopoietic precursor cells and their surrounding bone marrow environment are essential for erythroid differentiation as described in the model of the Sl/Sl d mouse, whose anemia results from bone marrow stromal defects. 2 In the bone marrow of mammals, erythropoiesis occurs in specific anatomic units called erythroblastic islands composed of a central macrophage surrounded by a ring of developing erythroblasts. [3][4][5] Under normal circumstances, only mature cells cross the endothelial barrier into peripheral blood; immature cells are retained within the bone marrow. 6 Little is known about the initial events leading to the formation of erythroblastic islands and about interactions between erythroid cells and endothelial cells.We have recently reported that neuropilin-1 is expressed on bone marrow stromal cells and that immature hematopoietic cells express several neuropilin-1 ligands. 7 Neuropilin-1 was first characterized as a receptor for the semaphorin/collapsin protein family, which plays an important role in the guidance of growing axons. 8,9 Recently, vascular endothelial growth factor A (VEGF-A) 10 and placenta growth factor (PlGF) 11 were also identified as neuropilin-1 ligands. VEGF-A is a homodimeric protein that contains 1 of the 5 VEGF isoforms composed of 121, 145, 165, 189, VEGF 189,. 12 These various isoforms differ in their affinity for heparin and extracellular matrix components and are important regulators of angiogenesis and blood vessel permeability. 13 They all bind the tyrosine kinase receptors, fetal liver kinase 1 (flk-1) 14 and fms-like tyrosine kinase 1 (flt-1). 15 Activation of flk-1 is correlated with the induction of angiogenesis and endothelial cell proliferation, 16,17 and activation of flt-1 enhances endothelial cell 17 and monocyte migration. 18,19 PlGF is a homodimeric protein that shares substantial structural similarity with VEGF-A. 20 Three PlGF isoforms have been described (PlGF-1, PlGF-2, and PlGF-3). 21,22 PlGF-2 differs from the other 2 as it contains a heparin-binding domain. 23 PlGFs do not interact with flk-1, but through binding to flt-1, 24 they can induce the migration of endothelial cells 25 and monocytes. 18,26 Their function in blood vessel permeability remains uncertain. 24,25,27 Finally, PlGF-1 can form active heterodimers with VEGF-A. 28 In a search for expression of neuropilin-1 ligands in hematopoietic cells, we discovered that erythroid cells, but not other mature hematopoietic cells, produce both VEGF-A and PlGF. We analyzed VEGF-A and PlGF secretion during in vitro erythroid differentiation and studied the effects of this production on monoc...