加拿大蒙特利尔临床研究所Hua Gu等研究人员合作发现，CBL和CBLB泛素连接酶的缺乏会通过减少BCL6的降解导致T滤泡辅助细胞反应亢进和红斑狼疮。相关论文于2024年5月17日在线发表在《免疫》杂志上。

研究人员发现，系统性红斑狼疮（SLE）患者的CD4⁺ T细胞中，泛素连接酶Casitas B lineage lymphoma（CBL）和CBLB（CBL）都出现了下调。T细胞特异性CBL缺陷小鼠会出现T滤泡辅助细胞（Tfh）细胞反应亢进和SLE，而阻断突变小鼠的Tfh细胞发育足以预防SLE。ICOS在SLE Tfh 细胞中上调，其信号通过伴侣介导的自噬（CMA）抑制BCL6降解，从而增加了BCL6。

相反，CBL则通过泛素化ICOS来抑制BCL6的表达。阻断BCL6降解足以增强Tfh细胞的反应。因此，CBL表达受损是SLE患者共有的普遍风险特征，也是Tfh细胞反应亢进和SLE的致病因素。ICOS-CBL轴可能是治疗SLE的靶点。

据介绍，最近的证据显示，SLE患者的Tfh反应亢进；然而，导致Tfh细胞反应亢进的分子机制以及它们是否会引起系统性红斑狼疮尚不清楚。

附：英文原文

Title: Deficiency of CBL and CBLB ubiquitin ligases leads to hyper T follicular helper cell responses and lupus by reducing BCL6 degradation

Author: Xin Li, Weili Sun, Mengxing Huang, Liying Gong, Xiaochen Zhang, Li Zhong, Virginie Calderon, Zhenhua Bian, Yi He, Woong-Kyung Suh, Yang Li, Tengfei Song, Yongrui Zou, Zhe-Xiong Lian, Hua Gu

Issue&Volume: 2024-05-17

Abstract: Recent evidence reveals hyper T follicular helper (Tfh) cell responses in systemiclupus erythematosus (SLE); however, molecular mechanisms responsible for hyper Tfhcell responses and whether they cause SLE are unclear. We found that SLE patientsdownregulated both ubiquitin ligases, casitas B-lineage lymphoma (CBL) and CBLB (CBLs),in CD4+ T cells. T cell-specific CBLs-deficient mice developed hyper Tfh cell responses andSLE, whereas blockade of Tfh cell development in the mutant mice was sufficient toprevent SLE. ICOS was upregulated in SLE Tfh cells, whose signaling increased BCL6by attenuating BCL6 degradation via chaperone-mediated autophagy (CMA). Conversely,CBLs restrained BCL6 expression by ubiquitinating ICOS. Blockade of BCL6 degradationwas sufficient to enhance Tfh cell responses. Thus, the compromised expression ofCBLs is a prevalent risk trait shared by SLE patients and causative to hyper Tfh cellresponses and SLE. The ICOS-CBLs axis may be a target to treat SLE.

DOI: 10.1016/j.immuni.2024.04.023

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00228-0