BackgroundSevere cutaneous adverse reactions (SCARs) mediated by cytotoxic T lymphocytes are a series of life‐threatening conditions with a mortality of 4%–20%. The clinical application of tumor necrosis factor‐alpha (TNF‐α) antagonist improves the outcome of some SCARs patients; however, this is complicated by the elusive and varied immunopathogenesis.AimTo investigate whether IgE antibody responses to HEMAs are associated with AD, its severity, and response to dupilumab.MethodsTo clarify the precise process and optimize the therapy regimen of SCARs, we performed single‐cell sequencing, in vitro functional and clinical analysis of patients with SCARs.ResultsWe observed that TNF‐α breaks drug‐specific T‐cell tolerance by inhibiting the expression of V‐type immunoglobulin domain‐containing suppressor of T‐cell activation (VISTA). Furthermore, TNF‐α generated a positive feedback loop in the early phase of drug‐specific T‐cell activation, whereby B cells acted reciprocally on the corresponding T cells to reinforce TNF‐α cytokine expression. In contrast, this pathway of TNF‐α‐VISTA signaling did not operate in memory effector T cells. Drug‐specific memory effector T‐cell responses were inhibited by increasing Treg cell expression in a negative feedback loop, with TNF‐α antagonists preventing the inhibitory effect. These observations align with the clinical analysis that early but not late intervention with TNF‐α antagonists significantly improved outcomes in SCARs patients.ConclusionOur findings defining feedback regulation of VISTA and Treg cells by TNF‐α in different stages of the drug‐specific T‐cell response and, indicate that a Treg agonists, instead of TNF‐α antagonists, could be used for treatment of patients with progressive SCARs.

中文翻译：

---

TNF-α 对 VISTA 和 Treg 的反馈调节控制药物过敏中 T 细胞反应


背景由细胞毒性 T 淋巴细胞介导的严重皮肤不良反应 （SCAR） 是一系列危及生命的疾病，死亡率为 4%-20%。肿瘤坏死因子-α （TNF-α） 拮抗剂的临床应用改善了一些 SCARs 患者的预后;然而，由于难以捉摸和不同的免疫发病机制，这变得复杂。目的研究 IgE 抗体对 HEMAs 的反应是否与 AD、其严重程度和对 dupilumab 的反应有关。方法为了阐明 SCARs 的精确过程并优化 SCARs 的治疗方案，我们对 SCARs 患者进行了单细胞测序、体外功能和临床分析。结果我们观察到 TNF α通过抑制 T 细胞活化抑制因子 （VISTA） 的表达来打破药物特异性 T 细胞耐受性。此外，TNF-α 在药物特异性 T 细胞活化的早期阶段产生了一个正反馈回路，其中 B 细胞相互作用于相应的 T 细胞以增强 TNF α细胞因子的表达。相比之下，TNF-α-VISTA 信号转导的这条通路在记忆效应 T 细胞中不起作用。通过在负反馈回路中增加 Treg 细胞表达来抑制药物特异性记忆效应 T 细胞反应，TNF α拮抗剂阻止抑制作用。这些观察结果与临床分析一致，即使用 TNF α 拮抗剂进行早期而非晚期干预可显著改善 SCARs 患者的预后。结论我们的研究结果定义了 TNF-α 在药物特异性 T 细胞反应的不同阶段对 VISTA 和 Treg 细胞的反馈调节，并表明 Treg 激动剂而不是 TNF α拮抗剂可用于治疗进行性 SCAR 患者。