刀豆球蛋白 A (ConA) 给药会引起小鼠快速而严重的肝损伤，而不变的自然杀伤 T (iNKT) 细胞被认为是该过程中的关键效应细胞。然而，潜在的调控机制尚不清楚。我们发现iNKT细胞组成型表达TIPE2（肿瘤坏死因子-α诱导蛋白8样2，或TNFAIPL2）。基因 TIPE2 消除使小鼠对 ConA 诱导的肝炎强烈敏感，并伴有 iNKT 细胞过度激活。此外，Tipe2-/-小鼠也更容易受到α-半乳糖神经酰胺（αGalCer）诱导的肝损伤，血清ALT水平升高，促炎细胞因子的产生增强。 CD1d 信号传导阻断或通过抗体消除 iNKT 细胞可降低 TIPE2 缺陷对肝损伤的影响。机制研究表明，iNKT 细胞中的 TIPE2 作为负调节因子，通过 PIP3-AKT/mTOR 途径限制 iNKT 细胞活性和细胞因子的产生。通过施用表达 TIPE2 的腺相关病毒进一步验证了 TIPE2 介导的肝损伤保护作用，可有效改善刀豆蛋白 A 诱导的肝损伤。然而，TIPE2 在另外两种肝损伤模型中是可有可无的，包括 D-GalN/LPS 和 APAP 诱导的肝炎。我们的研究结果揭示了 TIPE2 在减轻 iNKT 细胞介导的肝损伤中的新作用。我们认为 TIPE2 作为肝脏免疫稳态的重要调节剂，并可能用于治疗自身免疫性肝病。版权所有 © 2024 美国肝病研究协会。

Concanavalin A (ConA) administration induces a rapid and severe liver injury in mice, and invariant natural killer T (iNKT) cells are recognized to be the key effector cells in this process. However, the underlying regulatory mechanisms are not well defined.We found that iNKT cells constitutively expressed TIPE2 (Tumor necrosis factor-α-induced protein 8-like 2, or TNFAIPL2). Genetic TIPE2 ablation strongly sensitized mice to ConA-induced hepatitis, accompanied with hyperactivation of iNKT cells. Moreover, Tipe2-/- mice were also more susceptible to α-galactosylceramide (αGalCer)-induced liver injury, with elevated serum ALT level and enhanced proinflammatory cytokine production. CD1d signaling blockade or iNKT cell elimination through antibodies reduced the effect of TIPE2 deficiency on liver injury. Mechanistic studies revealed that TIPE2 in iNKT cells functioned as a negative regulator, limiting iNKT cell activity and cytokine production through PIP3- AKT/mTOR pathway. TIPE2-mediated protection from liver injury was further validated by the administration of adeno-associated viruses expressing TIPE2, which effectively ameliorated ConA-induced hepatic injury. However, TIPE2 was dispensable in two other liver injury models, including D-GalN/LPS and APAP-induced hepatitis.Our findings reveal a new role of TIPE2 in the attenuation of iNKT cell-mediated hepatic injury. We propose that TIPE2 serves as an important regulator of immune homeostasis in the liver, and might be exploited for the therapeutic treatment of autoimmune liver diseases.Copyright © 2024 American Association for the Study of Liver Diseases.