Galectin-1 and Semaphorin-3A Are Two Soluble Factors Conferring T-Cell Immunosuppression to Bone Marrow Mesenchymal Stem Cell

Abstract

In human physiology and animal models, bone marrow mesenchymal stem cells (MSCs) exert an immunosuppressive role in both in vitro and in vivo experiments. However, cellular and molecular mechanisms involved in this process are not clear and remain largely elusive. Several studies have suggested the implication of cell-cell contacts or soluble factors including transforming growth factor-b1 (TGF-b1), interleukin-10 (IL-10), indoleamine 2,3-dioxygenase (IDO), or human leukocyte antigen-G (HLA-G). Here, we show that both Galectin-1 and Semaphorin-3A (Sema-3A), 2 soluble factors capable to inhibit T-cell proliferation through neuropilin-1 (NP-1) binding, are highly expressed by MSCs and may account for their known suppressive activities. Furthermore, MSCs suppressive functions are completely reverted by soluble recombinant NP-1, the main receptor of both Galectin-1 and Sema-3A. Similar results were obtained by using blocking antibodies against Galectin-1 or Sema-3A. Taken together, these results demonstrate the critical role of Galectin-1 and Sema-3A in MSCs functions and may open new perspectives in the understanding and treatment of various immune and neoplastic disorders.

Measles virus modulates dendritic cell/T‐cell communication at the level of plexinA1/neuropilin‐1 recruitment and activity

“…Though it has not been directly addressed, interference with cytoskeletal dynamics might also account for the NP-1/SEMA3A-mediated loss of human thymocyte adhesion to thymic epithelial cells or their ECM-driven migration [35]. In line with our observations, inhibition of actin cytoskeletal rearrangement on NP-1 interaction with SEMA3A (the latter produced from mesenchymal stem cells or DC late after activation) has been linked to human T-cell immunosuppression [33,34]. A role for SEMA3A in termination of DC/T-cell interactions by repulsive destabilization of the conjugates on NP-1 interaction has been proposed [34], and in line with this, SEMA3A was produced only late after onset of allogeneic MLRs ( [34] and Fig.…”

“…4A and B). Collectively, MV infection of DC promotes release of a repulsive plexA1/NP-1 ligand, which, in co-cultures with T cells, occurs very early and to concentrations exceeding at least fivefold those described to inhibit TCR-stimulated T-cell expansion in vitro [33,34]. …”

“…Thus, plexinA1 (plexA1) and NP-1 were implicated in DC migration through endothelial layers and lymphatic entry [29], yet also in T-cell activation by murine or human DC [30][31][32], though neither their co-segregation at the IS nor their ligands there clearly identified. In contrast, the plexA1/NP-1 complex relays repulsive signals when exposed to soluble SEMA3A thereby causing loss of thymocyte adhesion, impairing actin cytoskeletal reorganization and activation of essential components of TCR signalling, or controlling Fas-mediated apoptosis [33][34][35][36][37]. Apparently, timely regulated IS recruitment and the respective interaction molecule essentially determine the ability of plexA1/ NP-1 to promote or terminate T-cell activation.…”

Immunogenicity and Immune-Modulating Properties of Human Stem Cells

“…Galectin-1 and semaphorin-3A (Sema-3A) are two soluble factors highly expressed by hMSC capable to inhibit T-cell proliferation through neuropilin-1 (NP-1). Blocking the interaction to NP-1 abolished hMSC immunosuppression (Lepelletier et al, 2010).…”

The Role of Mesenchymal Stem Cells in the Tumor Microenvironment

“…Several other factors are associated with the potential anti-inflammatory properties of MSCs including HLA-G, hepatocyte growth factor (HGF), leukemia inhibitory factor (LIF), IL1 receptor antagonist (IL1RA), CCL2, galectin-3, galectin-1 and semaphorin-3A, most of which attenuate T lymphocyte activation and are highly expressed by MSCs (Di Nicola, CarloStella et al 2002;Ortiz, Dutreil et al 2007;Di Ianni, Del Papa et al 2008;Kang, Kang et al 2008;Nasef, Ashammakhi et al 2008;Rafei, Hsieh et al 2008;Lepelletier, Lecourt et al 2009;Selmani, Naji et al 2009;Sioud, Mobergslien et al 2010;Volarevic, Al-Qahtani et al 2010). A recently advanced culprit is TNF--induced protein 6 TNAIP6 or TSG-6 (Lee, Pulin et al…”