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.

最近的证据揭示了系统性红斑狼疮 (SLE) 中滤泡辅助 T (Tfh) 细胞的高反应；然而，导致 Tfh 细胞过度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 CD4 ⁺ T 细胞中的泛素连接酶、casitas B 系淋巴瘤 (CBL) 和 CBLB (CBL) 均下调。 T 细胞特异性 CBL 缺陷小鼠出现过度 Tfh 细胞反应和 SLE，而突变小鼠中阻断 Tfh 细胞发育足以预防 SLE。 ICOS 在 SLE Tfh 细胞中上调，其信号传导通过伴侣介导的自噬 (CMA) 减弱 BCL6 降解来增加 BCL6。相反，CBL 通过泛素化 ICOS 来抑制 BCL6 表达。阻断 BCL6 降解足以增强 Tfh 细胞反应。因此，CBL 表达受损是 SLE 患者共有的一个普遍风险特征，也是高 Tfh 细胞反应和 SLE 的原因。 ICOS-CBLs 轴可能是治疗 SLE 的目标。