Semaphorin 3F and neuropilin-2 control the migration of human T-cell precursors.

Daniella Arêas Mendes-Da-Cruz,Pierre Milpied,Danielle Canioni,Wilson Savino,Nawel Bedjaoui,Elizabeth Macintyre,Carolina Valença Messias,Mireille Dardenne,Yves Lepelletier,Stéphane Leprêtre,Yves Bertrand,Karl Balabanian,Philippe Bousso,Norbert Ifrah,Olivier Hermine,Vahid Asnafi,Salete Smaniotto,Hervé Dombret,Amédée Renand ,Frédéric Baleydier ,Anne Brignier

doi:10.1371/journal.pone.0103405

Abstract

Neuropilins and semaphorins are known as modulators of axon guidance, angiogenesis, and organogenesis in the developing nervous system, but have been recently evidenced as also playing a role in the immune system. Here we describe the expression and role of semaphorin 3F (SEMA3F) and its receptor neuropilin-2 (NRP2) in human T cell precursors. NRP2 and SEMA3F are expressed in the human thymus, in both lymphoid and non-lymphoid compartments. SEMA3F have a repulsive effect on thymocyte migration and inhibited CXCL12- and sphingosine-1-phosphate (S1P)-induced thymocyte migration by inhibiting cytoskeleton reorganization prior to stimuli. Moreover, NRP2 and SEMA3F are expressed in human T-cell acute lymphoblastic leukemia/lymphoma primary cells. In these tumor cells, SEMA3F also blocks their migration induced by CXCL12 and S1P. Our data show that SEMA3F and NRP2 are further regulators of human thymocyte migration in physiological and pathological conditions.

Highlights

Thymocyte migration is critical for normal T cell development and maturation
NRP2 and semaphorin 3F (SEMA3F) are expressed in the human thymus We first observed that NRP2 and SEMA3F were constitutively expressed in developing human T cells in the thymus
The expression of both NRP2 and SEMA3F was widely observed in the epithelial cells as well as in non-epithelial components in thymic sections (Fig. 1a), as well as in primary thymic epithelial cells (TEC) cultures and a TEC cell line. mRNA expression of corresponding transcripts was quantified on thymocytes and in a TEC line (Fig. 1b)

Summary

Introduction

Thymocyte migration is critical for normal T cell development and maturation. From the entrance of precursors into the thymus, to the migration within the organ and mature thymocyte egress, several molecules and receptors are implicated, including extracellular matrix (ECM) molecules, chemokines, sphingosine-1phosfate (S1P) and their respective receptors. ECM proteins such as fibronectin and laminin are present in the thymus in different concentrations depending on the region. They are recognized by integrins constitutively expressed on thymocytes and microenvironmental cells. Besides thymocyte attraction, CXCR4 seems to play a role in the retention of immature CD4+CD8+ double-positive (DP) cells in the cortex [6]. Small concentrations of the natural S1P1 ligand, (S1P) promote lymphocyte migration, whereas therapeutic concentrations of FTY720 (a synthetic S1P agonist) inhibit lymphocyte egress from the thymus and peripheral lymphoid organs, inducing a cell sequestration in those organs and a profound lymphopenia [9,10,11]

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Conclusion