Department of Medicine and Surgery, University of Perugia, Perugia, Italy; Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
Immunity. 2022 Jun 14;55(6):1032-1050.e14. doi: 10.1016/j.immuni.2022.05.013.
Conventional dendritic cells (cDCs), cDC1 and cDC2, act both to initiate immunity and maintain self-tolerance. The tryptophan metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is used by cDCs in maintaining tolerance, but its role in different subsets remains unclear. At homeostasis, only mature CCR7 cDC1 expressed IDO1 that was dependent on IRF8. Lipopolysaccharide treatment induced maturation and IDO1-dependent tolerogenic activity in isolated immature cDC1, but not isolated cDC2. However, both human and mouse cDC2 could induce IDO1 and acquire tolerogenic function when co-cultured with mature cDC1 through the action of cDC1-derived l-kynurenine. Accordingly, cDC1-specific inactivation of IDO1 in vivo exacerbated disease in experimental autoimmune encephalomyelitis. This study identifies a previously unrecognized metabolic communication in which IDO1-expressing cDC1 cells extend their immunoregulatory capacity to the cDC2 subset through their production of tryptophan metabolite l-kynurenine. This metabolic axis represents a potential therapeutic target in treating autoimmune demyelinating diseases.
传统树突状细胞 (cDCs) 包括 cDC1 和 cDC2，它们既能启动免疫反应，又能维持自身耐受。色氨酸代谢酶吲哚胺 2,3-双加氧酶 1 (IDO1) 被 cDCs 用于维持耐受，但它在不同亚群中的作用尚不清楚。在稳态下，只有成熟的 CCR7+cDC1 表达依赖于 IRF8 的 IDO1。脂多糖处理诱导分离的未成熟 cDC1 成熟和 IDO1 依赖性致耐受性活性，但不诱导分离的 cDC2。然而，当与成熟的 cDC1 共培养时，人源和鼠源 cDC2 均可诱导 IDO1 并获得致耐受性功能，这是通过 cDC1 衍生的 l-犬尿氨酸发挥作用。因此，体内 cDC1 特异性 IDO1 失活可加重实验性自身免疫性脑脊髓炎的疾病。本研究鉴定了一种先前未被识别的代谢通讯，其中表达 IDO1 的 cDC1 细胞通过产生色氨酸代谢物 l-犬尿氨酸将其免疫调节能力扩展到 cDC2 亚群。该代谢轴代表了治疗自身免疫性脱髓鞘疾病的潜在治疗靶点。
