Intestinal mononuclear phagocytes (MPs) are composed of heterogeneous dendritic cell (DC) and macrophage subsets necessary for the initiation of immune response and control of inflammation. Although MPs in the normal intestine have been extensively studied, the heterogeneity and function of inflammatory MPs remain poorly defined. We performed phenotypical, transcriptional, and functional analyses of inflammatory MPs in infectious Salmonella colitis and identified CX3CR1+ MPs as the most prevalent inflammatory cell type. CX3CR1+ MPs were further divided into three distinct populations, namely, Nos2 +CX3CR1lo, Ccr7 +CX3CR1int (lymph migratory), and Cxcl13 +CX3CR1hi (mucosa resident), all of which were transcriptionally aligned with macrophages and derived from monocytes. In follow-up experiments in vivo, intestinal CX3CR1+ macrophages were superior to conventional DC1 (cDC1) and cDC2 in inducing Salmonella-specific mucosal IgA. We next examined spatial organization of the immune response induced by CX3CR1+ macrophage subsets and identified mucosa-resident Cxcl13 +CX3CR1hi macrophages as the antigen-presenting cells responsible for recruitment and activation of CD4+ T and B cells to the sites of Salmonella invasion, followed by tertiary lymphoid structure formation and the local pathogen-specific IgA response. Using mice we developed with a floxed Ccr7 allele, we showed that this local IgA response developed independently of migration of the Ccr7 +CX3CR1int population to the mesenteric lymph nodes and contributed to the total mucosal IgA response to infection. The differential activity of intestinal macrophage subsets in promoting mucosal IgA responses should be considered in the development of vaccines to prevent Salmonella infection and in the design of anti-inflammatory therapies aimed at modulating macrophage function in inflammatory bowel disease.

中文翻译：

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肠内驻留的CX3CR1hi巨噬细胞原位诱导三级淋巴结构和IgA反应。

肠道单核吞噬细胞（MPs）由异质树突状细胞（DC）和巨噬细胞亚群组成，这些亚群是引发免疫反应和控制炎症所必需的。尽管已经对正常肠道中的MP进行了广泛的研究，但炎症性MP的异质性和功能仍然不清楚。我们对感染性沙门氏菌结肠炎中的炎症性MP进行了表型，转录和功能分析，并将CX3CR1 + MPs确定为最普遍的炎症细胞类型。CX3CR1 + MP进一步分为三个不同的群体，即Nos2 + CX3CR1lo，Ccr7 + CX3CR1int（淋巴迁移）和Cxcl13 + CX3CR1hi（粘膜常住），所有这些均与巨噬细胞转录对齐并来源于单核细胞。在体内的后续实验中，肠道CX3CR1 +巨噬细胞在诱导沙门氏菌特异性粘膜IgA方面优于常规DC1（cDC1）和cDC2。接下来，我们检查了由CX3CR1 +巨噬细胞亚群诱导的免疫反应的空间组织，并确定了黏膜驻留的Cxcl13 + CX3CR1hi巨噬细胞为抗原呈递细胞，负责将CD4 + T和B细胞募集和激活到沙门氏菌入侵的部位，然后进行第三级淋巴样结构形成和局部病原体特异性IgA反应。使用我们用浮点的Ccr7等位基因开发的小鼠，我们发现该局部IgA反应独立于Ccr7 + CX3CR1int群体向肠系膜淋巴结的迁移而发展，并且对感染的总粘膜IgA反应做出了贡献。