Signal peptide peptidase-like 2a (SPPL2a) is an aspartyl intramembrane protease essential for degradation of the invariant chain CD74. In humans, absence of SPPL2a leads to Mendelian susceptibility to mycobacterial disease, which is attributed to a loss of the dendritic cell (DC) subset conventional DC2. In this study, we confirm depletion of conventional DC2 in lymphatic tissues of SPPL2a-/- mice and demonstrate dependence on CD74 using SPPL2a-/- CD74-/- mice. Upon contact with mycobacteria, SPPL2a-/- bone marrow-derived DCs show enhanced secretion of IL-1β, whereas production of IL-10 and IFN-β is reduced. These effects correlated with modulated responses upon selective stimulation of the pattern recognition receptors TLR4 and Dectin-1. In SPPL2a-/- bone marrow-derived DCs, Dectin-1 is redistributed to endosomal compartments. Thus, SPPL2a deficiency alters pattern recognition receptor pathways in a CD74-dependent way, shifting the balance from anti- to proinflammatory cytokines in antimycobacterial responses. We propose that in addition to the DC reduction, this altered DC functionality contributes to Mendelian susceptibility to mycobacterial disease upon SPPL2a deficiency.

中文翻译：

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膜内蛋白酶 SPPL2a 的缺乏改变了树突状细胞的抗分枝杆菌细胞因子反应

信号肽肽酶样 2a (SPPL2a) 是一种天冬氨酰膜内蛋白酶，对于降解不变链 CD74 至关重要。在人类中，SPPL2a 的缺失导致对分枝杆菌疾病的孟德尔易感性，这归因于树突状细胞 (DC) 子集常规 DC2 的丢失。在这项研究中，我们证实了 SPPL2a-/- 小鼠淋巴组织中常规 DC2 的消耗，并使用 SPPL2a-/- CD74-/- 小鼠证明了对 CD74 的依赖性。与分枝杆菌接触后，SPPL2a-/- 骨髓来源的 DC 显示 IL-1β 的分泌增强，而 IL-10 和 IFN-β 的产生减少。这些效应与模式识别受体 TLR4 和 Dectin-1 选择性刺激后的调节反应相关。在 SPPL2a-/- 骨髓来源的 DCs 中，Dectin-1 被重新分配到内体区室。因此，SPPL2a 缺陷以 CD74 依赖性方式改变模式识别受体通路，将抗分枝杆菌反应中的平衡从抗炎症细胞因子转变为促炎细胞因子。我们建议，除了 DC 减少之外，这种改变的 DC 功能有助于在 SPPL2a 缺乏时孟德尔对分枝杆菌疾病的易感性。