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Human Semaphorin-4A drives Th2 responses by binding to receptor ILT-4.

ABSTRACT: Semaphorin-4A (Sema4A) has been implicated in the co-stimulation of T cells and drives Th1 immune responses by binding to the receptor T-cell immunoglobulin and mucin domain protein 2 (Tim-2) in mice. Here we show that human, but not murine, Sema4A is preferentially expressed on antigen-presenting cells, and co-stimulates CD4+ T-cell proliferation and drives Th2 responses. By employing two independent cloning strategies, we demonstrate that Immunoglobulin-like transcript 4 (ILT-4) is a receptor for human SEMA4A (hSEMA4A) on activated CD4+ T cells. We also find hSEMA4A to be highly expressed in human asthmatic lung tissue, implying its potential function in disease pathogenesis. Our study defines a different biological function of hSEMA4A from its murine homolog through its binding to the receptor of ILT-4 to co-stimulate CD4+T cells and regulate Th2 cells differentiation.

SUBMITTER: Lu N

PROVIDER: S-EPMC5821868 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Human Semaphorin-4A drives Th2 responses by binding to receptor ILT-4.

Lu Ning N Li Ying Y Zhang Zhiqiang Z Xing Junji J Sun Ying Y Yao Sheng S Chen Lieping L

Nature communications 20180221 1

Semaphorin-4A (Sema4A) has been implicated in the co-stimulation of T cells and drives Th1 immune responses by binding to the receptor T-cell immunoglobulin and mucin domain protein 2 (Tim-2) in mice. Here we show that human, but not murine, Sema4A is preferentially expressed on antigen-presenting cells, and co-stimulates CD4<sup>+</sup> T-cell proliferation and drives Th2 responses. By employing two independent cloning strategies, we demonstrate that Immunoglobulin-like transcript 4 (ILT-4) is ...[more]

PMID: 29467366

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Semaphorin 4A Stabilizes Human Regulatory T Cell Phenotype via Plexin B1.

Project description:We previously reported that neuroimmune semaphorin (Sema) 4A regulates the severity of experimental allergic asthma and increases regulatory T (Treg) cell numbers in vivo; however, the mechanisms of Sema4A action remain unknown. It was also reported that Sema4A controls murine Treg cell function and survival acting through neuropilin 1 (NRP-1) receptor. To clarify Sema4A action on human T cells, we employed T cell lines (HuT78 and HuT102), human PBMCs, and CD4+ T cells in phenotypic and functional assays. We found that HuT78 demonstrated a T effector-like phenotype (CD4+CD25lowFoxp3-), whereas HuT102 expressed a Treg-like phenotype (CD4+CD25hi Foxp3+). Neither cell line expressed NRP-1. HuT102 cells expressed Sema4A counter receptor Plexin B1, whereas HuT78 cells were Sema4A+. All human peripheral blood CD4+ T cells, including Treg cells, expressed PlexinB1 and lacked both NRP-1 and -2. However, NRP-1 and Sema4A were detected on CD3negativeCD4intermediate human monocytes. Culture of HuT cells with soluble Sema4A led to an upregulation of CD25 and Foxp3 markers on HuT102 cells. Addition of Sema4A increased the relative numbers of CD4+CD25+Foxp3+ cells in PBMCs and CD4+ T cells, which were NRP-1negative but PlexinB1+, suggesting the role of this receptor in Treg cell stability. The inclusion of anti-PlexinB1 blocking Ab in cultures before recombinant Sema4A addition significantly decreased Treg cell numbers as compared with cultures with recombinant Sema4A alone. Sema4A was as effective as TGF-β in inducible Treg cell induction from CD4+CD25depleted cells but did not enhance Treg cell suppressive activity in vitro. These results suggest strategies for the development of new Sema4A-based therapeutic measures to combat allergic inflammatory diseases. ImmunoHorizons, 2019, 3: 71-87.

| S-EPMC6590919 | biostudies-literature

Semaphorin 4C: A Novel Component of B-Cell Polarization in Th2-Driven Immune Responses.

Project description:Semaphorins are important molecules in embryonic development and multiple semaphorins have been identified as having key roles in immune regulation. To date, there is little known about Semaphorin 4C (Sema4C) in immune biology. We report for the first time that Sema4C is inducible in human and murine B-cells and may be important for normal B-cell development.Human tonsillar B-cells were studied following activation via anti-CD40 antibodies in the presence or absence of representative Th1, Th2, and regulatory cytokines. Murine B-cells from WT and Sema4C-/- mice were similarly stimulated. B-cell phenotyping in WT and Sema4C mutant mice was performed by flow cytometry and lymphoid architecture was studied by immunohistochemistry. Sema4C expression and synapse formation were analyzed by confocal microscopy.Gene array studies performed on human tonsillar B-cells stimulated to produce IgE revealed that Sema4C was among the top genes expressed at 24?h, and the only semaphorin to be increased under Th2 conditions. Validation studies demonstrated that human and murine B-cells expressed Sema4C under similar conditions. Sema4C-/- mice had impaired maturation of B-cell follicles in spleens and associated decreases in follicular and marginal zone B-cells as well as impaired IgG and IgA production. In keeping with a potential role in maturation of B-cells, Sema4C was expressed predominantly on CD27+ human B-cells. Within 72?h of B-cell activation, Sema4C was localized to one pole in a synapse-like structure, in association with F-actin, B-cell receptor, and Plexin-B2. Cell polarization was impaired in Sema4C-/- mice.We have identified a novel immune semaphorin induced in human and murine B-cells under Th2 conditions. Sema4C appears to be a marker for human memory B-cells. It may be important for B-cell polarization and for the formation of normal splenic follicles.

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Neuroimmune semaphorin 4A as a drug and drug target for asthma.

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| S-EPMC3818409 | biostudies-literature

Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis.

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Helminth 2-Cys peroxiredoxin drives Th2 responses through a mechanism involving alternatively activated macrophages.

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Retrograde semaphorin-plexin signalling drives homeostatic synaptic plasticity.

Project description:Homeostatic signalling systems ensure stable but flexible neural activity and animal behaviour. Presynaptic homeostatic plasticity is a conserved form of neuronal homeostatic signalling that is observed in organisms ranging from Drosophila to human. Defining the underlying molecular mechanisms of neuronal homeostatic signalling will be essential in order to establish clear connections to the causes and progression of neurological disease. During neural development, semaphorin-plexin signalling instructs axon guidance and neuronal morphogenesis. However, semaphorins and plexins are also expressed in the adult brain. Here we show that semaphorin 2b (Sema2b) is a target-derived signal that acts upon presynaptic plexin B (PlexB) receptors to mediate the retrograde, homeostatic control of presynaptic neurotransmitter release at the neuromuscular junction in Drosophila. Further, we show that Sema2b-PlexB signalling regulates presynaptic homeostatic plasticity through the cytoplasmic protein Mical and the oxoreductase-dependent control of presynaptic actin. We propose that semaphorin-plexin signalling is an essential platform for the stabilization of synaptic transmission throughout the developing and mature nervous system. These findings may be relevant to the aetiology and treatment of diverse neurological and psychiatric diseases that are characterized by altered or inappropriate neural function and behaviour.

| S-EPMC5907800 | biostudies-literature

IL-21 receptor signalling partially mediates Th2-mediated allergic airway responses.

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| S-EPMC4083497 | biostudies-literature

Semaphorin-4A, an activator for T-cell-mediated immunity, suppresses angiogenesis via Plexin-D1.

Project description:Originally identified as axon guidance molecules, semaphorins are now known to be widely expressed mediators that play significant roles in immune responses and organ morphogenesis. However, not much is known about the signaling pathways via which they exert their organ-specific effects. Here we demonstrate that Sema4A, previously identified as an activator of T-cell-mediated immunity, is expressed in endothelial cells, where it suppresses vascular endothelial growth factor (VEGF)-mediated endothelial cell migration and proliferation in vitro and angiogenesis in vivo. Mice lacking Sema4A exhibit enhanced angiogenesis in response to VEGF or inflammatory stimuli. In addition, binding and functional experiments revealed Plexin-D1 to be a receptor for Sema4A on endothelial cells, indicating that Sema4A exerts organ-specific activities via different receptor-mediated signaling pathways: via Plexin-D1 in the endothelial cells and via T-cell immunoglobulin and mucin domain-2 in T cells. The effects of Sema4A on endothelial cells are dependent on its ability to suppress VEGF-mediated Rac activation and integrin-dependent cell adhesion. It thus appears that Sema4A-Plexin-D1 signaling negatively regulates angiogenesis.

| S-EPMC1817636 | biostudies-literature

Potentiation of regulatory T cell stability and function via a neuropilin-1:semaphorin-4a axis

Project description:Regulatory T cells (Treg) represent a critical immunoregulatory component of the immune system. The signals that maintain Treg stability and potentiate their function remain obscure. Here we show that the immune cell surface ligand semaphorin-4a (Sema4a)

2013-09-06 | GSE41185 | GEO

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