Semaphorin 4A Stabilizes Human Regulatory T Cell Phenotype via Plexin B1.
Semaphorin 4A Stabilizes Human Regulatory T Cell Phenotype via Plexin B1.
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DOI：
10.4049/immunohorizons.1800026
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发表时间：
2019-02-01
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影响因子：
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通讯作者：
Keegan, Achsah D
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作者：
Chapoval, Svetlana P;Hritzo, Molly;Keegan, Achsah D
我们以前报道，神经免疫信号蛋白（Sema）4A调节实验性过敏性哮喘的严重程度，并增加调节性T（Treg）细胞的数量在体内，然而，Sema 4A的作用机制仍然未知。还报道了Sema 4A通过神经纤毛蛋白1（NRP-1）受体控制鼠Treg细胞功能和存活。为了阐明Sema 4A对人T细胞的作用，我们在表型和功能测定中采用T细胞系（HuT 78和HuT 102）、人PBMC和CD 4 + T细胞。我们发现HuT 78表现出T效应子样表型（CD 4 + CD 25 lowFoxp 3-），而HuT 102表达Treg样表型（CD 4 + CD 25 hi Foxp 3+）。两种细胞系均不表达NRP-1。HuT 102细胞表达Sema 4A反受体丛蛋白B1，而HuT 78细胞为Sema 4A+。所有人外周血CD 4 + T细胞，包括Treg细胞，表达丛蛋白B1，缺乏NRP-1和-2。而NRP-1和Sema 4A在CD 3-CD 4中间型人单核细胞上被检测到。用可溶性Sema 4A培养HuT细胞导致HuT 102细胞上的CD 25和Foxp 3标志物上调。加入Sema 4A增加了PBMC和CD 4 + T细胞中CD 4 + CD 25 + Foxp 3+细胞的相对数量，这些细胞是NRP-1阴性但丛蛋白B1+，表明该受体在Treg细胞稳定性中的作用。与单独使用重组Sema 4A的培养物相比，在添加重组Sema 4A之前在培养物中包含抗丛蛋白B1阻断Ab显著降低了Treg细胞数量。Sema 4A在从CD 4 + CD 25耗尽的细胞诱导Treg细胞方面与TGF-β一样有效，但在体外不增强Treg细胞抑制活性。这些结果提示了开发新的基于Sema 4A的治疗措施以对抗过敏性炎症性疾病的策略。ImmunoHorizons，2019，3：71-87。
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-beta 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.