Abstract：
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.
摘要：
最近的证据揭示了系统性红斑狼疮（SLE）中的高T滤泡辅助（Tfh）细胞反应；然而，导致超Tfh细胞反应的分子机制以及它们是否导致SLE尚不清楚。我们发现SLE患者下调两种泛素连接酶，casitasB系淋巴瘤（CBL）和CBLB（CBL），在CD4+T细胞中。T细胞特异性CBLs缺陷小鼠出现了超Tfh细胞反应和SLE，而在突变小鼠中阻断Tfh细胞发育足以预防SLE。ICOS在SLETfh细胞中上调，其信号传导通过减弱通过伴侣介导的自噬（CMA）的BCL6降解来增加BCL6。相反，CBL通过泛素化ICOS抑制BCL6表达。阻断BCL6降解足以增强Tfh细胞应答。因此，CBL的表达受损是SLE患者共有的普遍风险特征,是Tfh细胞反应和SLE的病因.ICOS-CBL轴可以是治疗SLE的目标。
