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

Lü, Ning; Liu, Ying; Zhang, Zhiqiang; Xing, Junji; Sun, Ying; Yao, Sheng; Chen, Lieping

doi:10.1038/s41467-018-03128-9

Cited by 53 publications

(81 citation statements)

References 49 publications

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“…In this study we directly demonstrated a requisite role for Sema4A in the production of Th17, but not Th1 or Th2 cytokines, by human CD4+ T cells. In contrast with our observation, Sema4A was recently reported to induce proliferation and Th2 polarization in human CD4+ T cells . These differences may be attributed to the different recombinant Sema4A protein used, the different manner of CD4+ T cell activation and proliferation, and the use of CD4+ T cells from adult blood buffy coats.…”

Section: Discussioncontrasting

confidence: 99%

“…Our results show that all 3 of these receptors are involved in Sema4A signaling in CD4+ T cells, although the highest inhibition of Sema4A‐induced Th17 cytokine production was observed after the blocking of plexin D1. This finding might be explained simply by the fact that the percentage of CD4+ T cells expressing plexin D1 is much higher than those expressing plexin B2 and NRP‐1, but we cannot rule out the potential differential blocking efficiency of antibodies used, residual expression of plexin B2 following gene silencing, or involvement of immunoglobulin‐like transcript 4, a recently identified Sema4A receptor in CD4+ T cells .…”

Section: Discussionmentioning

confidence: 86%

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

Carvalheiro

Affandi

Malvar‐Fernández

et al. 2019

Arthritis & Rheumatology

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Objective To analyze the potential role of semaphorin 4A (Sema4A) in inflammatory and fibrotic processes involved in the pathology of systemic sclerosis (SSc). Methods Sema4A levels in the plasma of healthy controls (n = 11) and SSc patients (n = 20) were determined by enzyme‐linked immunosorbent assay (ELISA). The expression of Sema4A and its receptors in monocytes and CD4+ T cells from healthy controls and SSc patients (n = 6–7 per group) was determined by ELISA and flow cytometry. Th17 cytokine production by CD4+ T cells (n = 5–7) was analyzed by ELISA and flow cytometry. The production of inflammatory mediators and extracellular matrix (ECM) components by dermal fibroblast cells (n = 6) was analyzed by quantitative polymerase chain reaction, ELISA, Western blotting, confocal microscopy, and ECM deposition assay. Results Plasma levels of Sema4A, and Sema4A expression by circulating monocytes and CD4+ T cells, were significantly higher in SSc patients than in healthy controls (P < 0.05). Inflammatory mediators significantly up‐regulated the secretion of Sema4A by monocytes and CD4+ T cells from SSc patients (P < 0.05 versus unstimulated SSc cells). Functional assays showed that Sema4A significantly enhanced the expression of Th17 cytokines induced by CD3/CD28 in total CD4+ T cells as well in different CD4+ T cell subsets (P < 0.05 versus unstimulated SSc cells). Finally, Sema4A induced a profibrotic phenotype in dermal fibroblasts from both healthy controls and SSc patients, which was abrogated by blocking or silencing the expression of Sema4A receptors. Conclusion Our findings indicate that Sema4A plays direct and dual roles in promoting inflammation and fibrosis, 2 main features of SSc, suggesting that Sema4A might be a novel therapeutic target in SSc.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 86%

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

Carvalheiro

Affandi

Malvar‐Fernández

et al. 2019

Arthritis & Rheumatology

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“…The role of Plexin B1 in CD4 + T cell differentiation and function has not been examined before, to our knowledge. Moreover, a novel Sema4A receptor Ig-like transcript 4 (ILT-4) has been recently cloned, and its functional activity on CD4 + T cells has been examined (58). Naive CD4 + T cells were cocultured with hSema4A-expressing L cells in the presence of T cell-activating factors, immobilized anti-CD3 and anti-CD28 Abs, or under Th1-or Th2-skewing conditions.…”

Section: Discussionmentioning

confidence: 99%

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

Chapoval

Hritzo

et al. 2019

ImmunoHorizons

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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 + CD25 low Foxp3 2), whereas HuT102 expressed a Treg-like phenotype (CD4 + CD25 hi 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 CD3 negative CD4 intermediate 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-1 negative 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-b in inducible Treg cell induction from CD4 + CD25 depleted 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.

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“…4d, e). Recently, Lu et al reported that human Sema4A regulate Th2 differentiation [17]. We analyzed IL-4 level in the sera and GATA3 expression in CD4+ T cells in RRMS patients.…”

Section: Rrms Patients With High Sema4a Levels Present Th17 But Not Tmentioning

confidence: 95%

Sema4A is implicated in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase

Koda

Namba

Kinoshita

et al. 2020

J Neuroinflammation

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Background: Sema4A is a regulator of helper T cell (Th) activation and differentiation in the priming phase, which plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). However, the role of Sema4A in the effector phase remains elusive. We aimed to investigate the role of Sema4A at the effector phase in adoptively transferred EAE model. Clinical features and cytokine profiles of MS patients with high Sema4A levels were also examined in detail to clarify the correlation between Sema4A levels and disease activity of patients with MS. Methods: We adoptively transferred encephalitogenic Th1 or Th17 cells to wild type (WT) or Sema4A-deficient (Sema4A KO) mice and assessed severity of symptoms and cellular infiltration within the central nervous system (CNS). In addition, we analyzed clinical and radiological features (n = 201), levels of serum IFN-γ and IL-17A (n = 86), complete remission ratio by IFN-β (n = 38) in all of relapsing-remitting multiple sclerosis (RRMS) patients enrolled in this study. Results: Sema4A KO recipient mice receiving Th17-skewed WT myelin oligodendrocyte glycoprotein (MOG)-specific encephalitogenic T cells showed a significant reduction in the clinical score compared to the WT recipient mice. However, Sema4A KO recipient mice showed similar disease activity to the WT recipient mice when transferred with Th1-skewed encephalitogenic T cells. Bone marrow chimeric study indicated that Sema4A expressed on hematopoietic cells, but not the CNS resident cells, are responsible for augmenting Th17-mediated neuroinflammation. Additionally, in contrast to comparable IFN-γ levels, IL-17A is significantly higher in RRMS patients with high Sema4A level than those with low Sema4A patients with high Sema4A levels showed earlier disease onset, more severe disease activity and IFN-β unresponsiveness than those with low Sema4A levels.

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

Cited by 53 publications

References 49 publications

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

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

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

Sema4A is implicated in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase

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