意大利佩鲁贾大学Francesca Fallarino、美国圣路易斯华盛顿大学Kenneth M. Murphy等研究人员合作发现，成熟cDC1中吲哚胺2,3-二氧酶1的激活通过代谢交流促进炎症性cDC2的耐受原性训练。相关论文于2022年6月14日发表在《免疫》杂志上。

据研究人员介绍，经典树突状细胞（cDC），cDC1和cDC2，既能启动免疫又能维持自我耐受。色氨酸代谢酶吲哚胺2,3-二氧酶1（IDO1）被cDC用于维持耐受性，但其在不同亚群中的作用仍不清楚。

研究人员发现，在平衡状态下，只有成熟的CCR7⁺cDC1表达IDO1，它依赖于IRF8。脂多糖处理可诱导成熟和IDO1依赖性的耐受性活动，但不包括分离的cDC1。然而，人类和小鼠的cDC2在与成熟的cDC1共同培养时，通过cDC1衍生的l-犬尿氨酸的作用，可以诱导IDO1并获得致容功能。因此，在实验性自身免疫性脑脊髓炎中，cDC1特异性失活的IDO1在体内加重了疾病。

这项研究确定了一个以前未被认识的代谢交流，其中表达IDO1的cDC1细胞通过生产色氨酸代谢物l-犬尿氨酸，将其免疫调节能力扩展到cDC2亚群。这一代谢轴代表了治疗自身免疫性脱髓鞘疾病的一个潜在治疗靶标。

附：英文原文

Title: Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication

Author: Marco Gargaro, Giulia Scalisi, Giorgia Manni, Carlos G. Briseo, Prachi Bagadia, Vivek Durai, Derek J. Theisen, Sunkyung Kim, Marilena Castelli, Chenling A. Xu, Gerd Meyer zu Hrste, Giuseppe Servillo, Maria A. Della Fazia, Giulia Mencarelli, Doriana Ricciuti, Eleonora Padiglioni, Nicola Giacchè, Carolina Colliva, Roberto Pellicciari, Mario Calvitti, Teresa Zelante, Dietmar Fuchs, Ciriana Orabona, Louis Boon, Alban Bessede, Marco Colonna, Paolo Puccetti, Theresa L. Murphy, Kenneth M. Murphy, Francesca Fallarino

Issue&Volume: 2022/06/14

Abstract: 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.

DOI: 10.1016/j.immuni.2022.05.013

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00233-3