Migrating Type 2 Dendritic Cells Prime Mucosal Th17 Cells Specific to Small Intestinal Commensal Bacteria.
Migrating Type 2 Dendritic Cells Prime Mucosal Th17 Cells Specific to Small Intestinal Commensal Bacteria.
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DOI：
10.4049/jimmunol.2200204
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发表时间：
2022-09-15
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树突状细胞 (DC) 是专业的抗原呈递细胞，配备有 MHC 限制性抗原、共刺激和细胞因子，可有效启动幼稚 T 细胞并将其分化为不同的功能子集。 DC携带的免疫信号反映了抗原摄取的途径和它们接受的先天刺激。在粘膜组织中，由于外来抗原和炎症信号的多样性，DCs主要被激活和迁移。在小肠中，CD4 Th17 细胞丰富，并且已被证明受到 DC 和巨噬细胞的调节。使用小鼠共生细菌实验模型，我们发现共生驱动的 Th17 细胞的早期启动步骤是由真正表达 Zbtb46 的 DC 控制的。 DC2 从小肠到肠系膜淋巴结的 CCR7 依赖性迁移对于初始 CD4 T 细胞的激活至关重要。 MLN 中的迁移 DC2 群体几乎全部是 Esam+ 细胞。单细胞 RNA 测序强调了 MLN 迁移 DC 上丰富的共刺激标记（CD40 和 OX40）和趋化因子（Ccl22 和 Cxcl16）。 MLN 迁移 DC2 的进一步解析揭示了 Th17 极化细胞因子 IL-6 与表达 CD40、Ccl17 和 Ccl22 的 DC2 共定位。因此，早期 Th17 细胞分化是由肠道引流淋巴结中一小部分迁移 DC2 启动的。
Dendritic cells (DCs) are professional antigen-presenting cells equipped with MHC-restricted antigens, co-stimulations, and cytokines that effectively prime and differentiate naïve T cells into distinct functional subsets. The immune signals that DCs carry reflect the route of antigen uptake and the innate stimuli they received. In the mucosal tissues, owing to the great variety of foreign antigens and inflammatory cues, DCs are predominantly activated and migratory. In the small intestine, CD4 Th17 cells are abundant and have been shown to be regulated by DCs and macrophages. Using a mouse commensal bacteria experimental model, we identified that the early priming step of commensal-driven Th17 cells is controlled by bona fide Zbtb46-expressing DCs. CCR7-dependent migration of DC2s from the small intestine to the mesenteric lymph nodes is essential for the activation of naïve CD4 T cells. The migratory DC2 population in the MLN are almost exclusively Esam+ cells. Single-cell RNA sequencing highlighted the abundance of co-stimulatory markers (CD40 and OX40) and chemokines (Ccl22 and Cxcl16) on MLN migratory DCs. Further resolution of MLN migratory DC2s revealed that the Th17-polarizing cytokine IL-6 colocalizes with DC2s expressing CD40, Ccl17, and Ccl22. Thus, early Th17 cell differentiation is initiated by a small subset of migratory DC2s in the gut draining lymph nodes.