Max Planck Institute for Immunobiology and Epigenetics, Freiburg 79108, Germany; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Max Planck Institute for Immunobiology and Epigenetics, Freiburg 79108, Germany.
Immunity. 2021 Nov 9;54(11):2514-2530.e7. doi: 10.1016/j.immuni.2021.10.009. Epub 2021 Oct 29.
Human plasmacytoid dendritic cells (pDCs) are interleukin-3 (IL-3)-dependent cells implicated in autoimmunity, but the role of IL-3 in pDC biology is poorly understood. We found that IL-3-induced Janus kinase 2-dependent expression of SLC7A5 and SLC3A2, which comprise the large neutral amino acid transporter, was required for mammalian target of rapamycin complex 1 (mTORC1) nutrient sensor activation in response to toll-like receptor agonists. mTORC1 facilitated increased anabolic activity resulting in type I interferon, tumor necrosis factor, and chemokine production and the expression of the cystine transporter SLC7A11. Loss of function of these amino acid transporters synergistically blocked cytokine production by pDCs. Comparison of in vitro-activated pDCs with those from lupus nephritis lesions identified not only SLC7A5, SLC3A2, and SLC7A11 but also ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2) as components of a shared transcriptional signature, and ENPP2 inhibition also blocked cytokine production. Our data identify additional therapeutic targets for autoimmune diseases in which pDCs are implicated.
人类浆细胞样树突状细胞（pDCs）是白细胞介素 3（IL-3）依赖性细胞，与自身免疫有关，但 IL-3 在 pDC 生物学中的作用知之甚少。我们发现，IL-3 诱导的 Janus 激酶 2 依赖性 SLC7A5 和 SLC3A2 的表达，组成了大分子中性氨基酸转运体，对于哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）营养传感器在 Toll 样受体激动剂作用下的激活是必需的。mTORC1 促进了增加的合成代谢活性，导致 I 型干扰素、肿瘤坏死因子和趋化因子的产生以及胱氨酸转运蛋白 SLC7A11 的表达。这些氨基酸转运体的功能丧失协同阻断 pDC 细胞的细胞因子产生。体外激活的 pDCs 与狼疮肾炎病变中的 pDCs 进行比较，不仅鉴定了 SLC7A5、SLC3A2 和 SLC7A11，还鉴定了核苷酸焦磷酸酶-磷酸二酯酶 2（ENPP2）作为共享转录特征的组成部分，并且 ENPP2 抑制也阻断了细胞因子的产生。我们的数据确定了自身免疫性疾病中 pDCs 涉及的其他治疗靶点。
