■泛素特异性蛋白酶(USP),超过50种去泛素酶蛋白的一大子集,最近已成为癌症的有希望的靶标。然而,它们在免疫细胞调节中的作用,特别是在T细胞活化中,分化,和效应器函数,在很大程度上仍未探索。
■我们利用USP28敲除小鼠系来研究USP28对T细胞活化和功能的影响,以及使用葡聚糖硫酸钠(DSS)诱导的结肠炎模型和一系列体外测定在肠道炎症中的作用。
■我们的结果表明,USP28对急性肠道炎症具有保护作用。机械上,USP28敲除小鼠(USP28-/-)表现出总T细胞的增加,这主要是由于CD8+T细胞含量增加。此外,USP28缺乏导致T细胞活化和功能改变的早期缺陷。具体来说,我们观察到IL17的表达降低和诱导型调节性T(iTreg)抑制功能的增加。重要的是,缺乏USP28的活化T细胞显示STAT5磷酸化增加.与这些发现一致,这些小鼠对急性DSS诱导的肠道炎症的易感性增加,伴有升高的IL22细胞因子水平。
■我们的研究结果表明,USP28对T细胞功能至关重要,并通过调节STAT5信号传导和IL22的产生来保护小鼠免受急性DSS诱导的结肠炎。作为T细胞调节因子,USP28在免疫反应和肠道健康中起着至关重要的作用。
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.