Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, University of Gdańsk, Gdańsk, Poland.
Front Immunol. 2024 Jul 15;15:1401949. doi: 10.3389/fimmu.2024.1401949. eCollection 2024.
Ubiquitin-specific proteases (USPs), a large subset of more than 50 deubiquitinase proteins, have recently emerged as promising targets in cancer. However, their role in immune cell regulation, particularly in T cell activation, differentiation, and effector functions, remains largely unexplored.
We utilized a USP28 knockout mouse line to study the effect of USP28 on T cell activation and function, and its role in intestinal inflammation using the dextran sulfate sodium (DSS)-induced colitis model and a series of in vitro assays.
Our results show that USP28 exerts protective effects in acute intestinal inflammation. Mechanistically, USP28 knockout mice (USP28-/-) exhibited an increase in total T cells mainly due to an increased CD8+ T cell content. Additionally, USP28 deficiency resulted in early defects in T cell activation and functional changes. Specifically, we observed a reduced expression of IL17 and an increase in inducible regulatory T (iTreg) suppressive functions. Importantly, activated T cells lacking USP28 showed increased STAT5 phosphorylation. Consistent with these findings, these mice exhibited increased susceptibility to acute DSS-induced intestinal inflammation, accompanied by elevated IL22 cytokine levels.
Our findings demonstrate that USP28 is essential for T cell functionality and protects mice from acute DSS-induced colitis by regulating STAT5 signaling and IL22 production. As a T cell regulator, USP28 plays a crucial role in immune responses and intestinal health.
泛素特异性蛋白酶（USP）是超过 50 种去泛素化酶蛋白中的一个重要亚类，最近已成为癌症治疗的一个有前途的靶点。然而，它们在免疫细胞调节中的作用，特别是在 T 细胞激活、分化和效应功能方面，仍在很大程度上未被探索。
我们利用 USP28 敲除小鼠模型来研究 USP28 对 T 细胞激活和功能的影响，以及其在葡聚糖硫酸钠（DSS）诱导的结肠炎模型和一系列体外实验中在肠道炎症中的作用。
我们的结果表明，USP28 在急性肠道炎症中发挥保护作用。从机制上讲，USP28 敲除小鼠（USP28-/-）表现出总 T 细胞的增加，主要是由于 CD8+T 细胞含量增加。此外，USP28 缺失导致 T 细胞激活和功能变化的早期缺陷。具体来说，我们观察到 IL17 的表达减少和诱导性调节 T（iTreg）抑制功能增加。重要的是，缺乏 USP28 的活化 T 细胞显示出 STAT5 磷酸化增加。与这些发现一致的是，这些小鼠表现出对急性 DSS 诱导的肠道炎症的易感性增加，同时伴有 IL22 细胞因子水平的升高。
我们的研究结果表明，USP28 对于 T 细胞功能是必需的，通过调节 STAT5 信号通路和 IL22 的产生，保护小鼠免受急性 DSS 诱导的结肠炎。作为 T 细胞调节剂，USP28 在免疫反应和肠道健康中起着关键作用。
