Tumor necrosis factor receptor family costimulation increases regulatory T-cell activation and function via NF-κB.,European Journal of Immunology

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Tumor necrosis factor receptor family costimulation increases regulatory T-cell activation and function via NF-κB.
European Journal of Immunology ( IF 4.5 ) Pub Date : 2020-02-03 , DOI: 10.1002/eji.201948393
Martina Lubrano di Ricco ₁ , Emilie Ronin ₁ , Davi Collares ₂ , Jordane Divoux ₁ , Sylvie Grégoire ₁ , Harald Wajant ₃ , Tomás Gomes ₄ , Yenkel Grinberg-Bleyer ₅ , Véronique Baud ₂ , Gilles Marodon ₁ , Benoît L Salomon ₁

Affiliation

Several drugs targeting members of the TNF superfamily or TNF receptor superfamily (TNFRSF) are widely used in medicine or are currently being tested in therapeutic trials. However, their mechanism of action remains poorly understood. Here, we explored the effects of TNFRSF co‐stimulation on murine Foxp3⁺ regulatory T cell (Treg) biology, as they are pivotal modulators of immune responses. We show that engagement of TNFR2, 4‐1BB, GITR, and DR3, but not OX40, increases Treg proliferation and survival. Triggering these TNFRSF in Tregs induces similar changes in gene expression patterns, suggesting that they engage common signal transduction pathways. Among them, we identified a major role of canonical NF‐κB. Importantly, TNFRSF co‐stimulation improves the ability of Tregs to suppress colitis. Our data demonstrate that stimulation of discrete TNFRSF members enhances Treg activation and function through a shared mechanism. Consequently, therapeutic effects of drugs targeting TNFRSF or their ligands may be mediated by their effect on Tregs.

中文翻译：

肿瘤坏死因子受体家族的共同刺激通过NF-κB增加了调节性T细胞的活化和功能。

靶向TNF超家族或TNF受体超家族（TNFRSF）成员的几种药物已广泛用于药物中或目前正在治疗性试验中进行测试。但是，它们的作用机理仍然知之甚少。在这里，我们探讨了TNFRSF共刺激对小鼠Foxp3 ^+的影响调节性T细胞（Treg）生物学，因为它们是免疫反应的关键调节剂。我们发现TNFR2、4-1BB，GITR和DR3而不是OX40的参与增加了Treg的增殖和存活。在Tregs中触发这些TNFRSF会诱导基因表达模式的类似变化，表明它们参与了常见的信号转导途径。其中，我们确定了经典的NF-κB的主要作用。重要的是，TNFRSF的共同刺激可提高Tregs抑制结肠炎的能力。我们的数据表明，离散TNFRSF成员的刺激通过共享机制增强Treg激活和功能。因此，靶向TNFRSF或其配体的药物的治疗作用可以通过其对Treg的作用来介导。

更新日期：2020-02-03

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