In celiac disease (CeD), a gluten-dependent autoimmune disorder, transglutaminase 2 (TG2) deamidates selected glutamine residues in gluten peptides, while HLA-DQ2 presents deamidated antigens to inflammatory T cells. The cellular sources of pathogenic TG2 and DQ2 are unclear. Using chemical biology tools, we show that intestinal CD103 ⁺ dendritic cells (DCs) couple cell-surface TG2 to the endocytic LRP1 receptor to simultaneously deamidate gluten antigens and concentrate them in lysosomes. In DQ2-transgenic mice, CD103 ⁺ DCs loaded with deamidated antigens migrate from intestinal lamina propria and Peyer's patches into mesenteric lymph nodes, where they engage T cells. In turn, gluten antigen presentation upregulates intestinal TG2 activity. The tool (HB-230) used to establish a role of CD103 ⁺ DCs in gluten antigen presentation and TG2 activation in mice also revealed that the TG2/LRP1 pathway is active in human CD14 ⁺ monocytes. Within this population of circulating monocytes, a DC subset with the gut-homing β7-integrin marker is elevated in CeD patients with active disease compared to non-celiac controls or patients on a gluten-free diet. Our findings not only inform the cellular basis for gluten toxicity in CeD but they also highlight the immunologic role of an enigmatic protein of growing therapeutic relevance in CeD and other immune disorders.

在乳糜泻（CeD）中，这是一种依赖于麸质的自身免疫性疾病，转谷氨酰胺酶2（TG2）将特定的谷氨酰胺残基脱酰胺化为麦胶肽，而HLA-DQ2则向炎症T细胞呈递脱酰胺化的抗原。导致疾病的TG2和DQ2的具体细胞来源尚不清楚。通过使用化学生物学工具，我们发现肠道CD103+树突状细胞（DCs）将细胞表面的TG2与内吞LRP1受体偶联起来，以同时对麸质抗原进行脱酰胺化并将其集中到溶酶体中。在DQ2转基因小鼠中，携带脱酰胺化抗原的CD103+ DCs从肠道固有层和派耶氏斑迁移到肠系膜淋巴结，在那里它们与T细胞相互作用。反过来，麸质抗原呈递上调了肠道中的TG2活性。用于在小鼠中建立CD103+ DCs在麸质抗原呈递和TG2激活方面的作用的工具（HB-230）还揭示了TG2/LRP1途径在人类CD14+单核细胞中的活性。在这类循环单核细胞中，具有肠道归巢β7整合素标记物的DC亚群在活动性乳糜泻患者中比非乳糜泻对照组或无麸质饮食患者的水平更高。我们的研究不仅阐明了CeD中麸质毒性的细胞基础，还强调了一个对CeD及其他免疫性疾病具有日益重要的治疗意义但至今仍充满神秘色彩的蛋白质的免疫学作用。