Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China; Montreal Clinical Research Institute, Montreal, QC H2W 1R7, Canada; Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada.
Montreal Clinical Research Institute, Montreal, QC H2W 1R7, Canada; Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada.
Immunity. 2024 Jul 9;57(7):1603-1617.e7. doi: 10.1016/j.immuni.2024.04.023. Epub 2024 May 17.
Recent evidence reveals hyper T follicular helper (Tfh) cell responses in systemic lupus erythematosus (SLE); however, molecular mechanisms responsible for hyper Tfh cell responses and whether they cause SLE are unclear. We found that SLE patients downregulated 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 and SLE, whereas blockade of Tfh cell development in the mutant mice was sufficient to prevent SLE. ICOS was upregulated in SLE Tfh cells, whose signaling increased BCL6 by attenuating BCL6 degradation via chaperone-mediated autophagy (CMA). Conversely, CBLs restrained BCL6 expression by ubiquitinating ICOS. Blockade of BCL6 degradation was sufficient to enhance Tfh cell responses. Thus, the compromised expression of CBLs is a prevalent risk trait shared by SLE patients and causative to hyper Tfh cell responses and SLE. The ICOS-CBLs axis may be a target to treat SLE.
最近的证据表明，系统性红斑狼疮（SLE）中存在滤泡辅助性 T 细胞（Tfh）反应过度；然而，导致 Tfh 细胞反应过度的分子机制以及它们是否会导致 SLE 尚不清楚。我们发现，SLE 患者的 CD4 T 细胞中两种泛素连接酶， Casitas B 细胞淋巴瘤（CBL）和 CBLB（CBLs）均下调。T 细胞特异性 CBLs 缺失的小鼠会出现 Tfh 细胞反应过度和 SLE，而在突变小鼠中阻断 Tfh 细胞的发育足以预防 SLE。SLE Tfh 细胞中 ICOS 上调，其信号通过伴侣蛋白介导的自噬（CMA）减弱 BCL6 降解来增加 BCL6。相反，CBLs 通过泛素化 ICOS 来抑制 BCL6 的表达。阻断 BCL6 降解足以增强 Tfh 细胞反应。因此，CBLs 的表达缺陷是 SLE 患者的普遍风险特征，导致 Tfh 细胞反应过度和 SLE。ICOS-CBLs 轴可能是治疗 SLE 的一个靶点。
