Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, Linhai, China.
Department of Pathology, Affiliated Taizhou Hospital of Wenzhou Medical University, Linhai, China.
FEBS Open Bio. 2021 May;11(5):1406-1416. doi: 10.1002/2211-5463.13148. Epub 2021 Apr 1.
T-cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates T-cell suppression in various autoimmune diseases, such as chronic inflammatory liver disease. However, the regulatory effect of Tim-3 on Th17 cells in autoimmune hepatitis (AIH) is incompletely understood. Here, we studied the expression and function of Tim-3 in T cells in AIH patients and in a Con A (concanavalin A)-induced mouse AIH model. We report that the frequency of CD4 Tim-3 T cells in peripheral blood samples of AIH patients was lower than that in the control group. The p38/MKP-1 and p-JNK pathways were activated, and the expression of interleukin-17A protein was elevated in patients with AIH. Furthermore, the extent of pathological damage in the livers of mice with a blocked Tim-3 signaling pathway (anti-Tim-3 group) was markedly increased and correlated with elevated alanine aminotransferase and aspartate aminotransferase levels. In addition, the frequency of CD4 IL-17 T (Th17) cells in the anti-Tim-3 group was increased, while that in mice with blocked p38 activity was decreased. Finally, the expression of MKP-1 (p-p38) gradually increased in the control, Con A, and anti-Tim-3 groups, but the levels of interleukin-17A were decreased in the p38-blocked group. In summary, our results suggest that Tim-3 suppresses AIH by regulating Th17 cells through the p38/MKP-1 pathway.
T 细胞免疫球蛋白和粘蛋白结构域分子 3（Tim-3）在各种自身免疫性疾病中介导 T 细胞抑制作用，如慢性炎症性肝病。然而，Tim-3 对自身免疫性肝炎（AIH）中 Th17 细胞的调节作用尚不完全清楚。在这里，我们研究了 AIH 患者和 ConA（刀豆球蛋白 A）诱导的小鼠 AIH 模型中 T 细胞中 Tim-3 的表达和功能。我们报告称，AIH 患者外周血样本中 CD4 Tim-3 T 细胞的频率低于对照组。p38/MKP-1 和 p-JNK 通路被激活，并且 AIH 患者中白细胞介素-17A 蛋白的表达升高。此外，阻断 Tim-3 信号通路（抗 Tim-3 组）的小鼠肝脏的病理损伤程度显著增加，并与丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平升高相关。此外，抗 Tim-3 组中 CD4 IL-17 T（Th17）细胞的频率增加，而阻断 p38 活性的小鼠中则减少。最后，MKP-1（p-p38）的表达在对照组、ConA 和抗 Tim-3 组中逐渐增加，但 p38 阻断组中白细胞介素-17A 的水平降低。总之，我们的结果表明，Tim-3 通过 p38/MKP-1 通路调节 Th17 细胞来抑制 AIH。
