Gut-resident CX3CR1hi macrophages induce tertiary lymphoid structures and IgA response in situ
Gut-resident CX3CR1hi macrophages induce tertiary lymphoid structures and IgA response in situ
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DOI：
10.1126/sciimmunol.aax0062
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发表时间：
2020-04-01
影响因子：
24.8
通讯作者：
Bogunovic, Milena
中科院分区：
文献类型：
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作者：
Koscso, Balazs;Kurapati, Sravya;Bogunovic, Milena
肠道单核巨噬细胞(MPS)由异质树突状细胞(DC)和巨噬细胞亚群组成，是启动免疫反应和控制炎症所必需的。尽管对正常肠道中的MPS进行了广泛的研究，但炎性MPS的异质性和功能仍不清楚。我们对感染性沙门氏菌结肠炎的炎性MPS进行了表型、转录和功能分析，发现CX3CR1(+)MPS是最常见的炎性细胞类型。CX3CR1(+)MPS进一步分为三个不同的群体，即Nos(2+)CX3CR1(Lo)，Ccr(7+)CX3CR1(Int)(淋巴迁移性)和CxCL(13+)CX3CR1(Hi)(粘膜驻留)，它们都与巨噬细胞转录序列一致，均来自单核细胞。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黏膜IgA方面优于传统的DC1(CDC1)和cDC2。接下来，我们研究了CX3CR1(+)巨噬细胞亚群诱导的免疫反应的空间组织，并确定驻留在粘膜上的CxCl73(+)CX3CR1(Hi)巨噬细胞是负责招募和激活CD4(+)T和B细胞到沙门氏菌入侵部位的抗原提呈细胞，随后是第三级淋巴结构形成和局部病原体特异性IgA反应。使用我们培育的CCR7等位基因的小鼠，我们发现这种局部的IgA反应独立于CCR7(+)CX3CR1(INT)群体向肠系膜淋巴结的迁移而发展，并有助于总的粘膜对感染的IgA反应。在开发预防沙门氏菌感染的疫苗和设计旨在调节炎症性肠病巨噬细胞功能的抗炎疗法时，应考虑肠道巨噬细胞亚群在促进粘膜IgA反应方面的不同活性。
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, Nos(2+)CX3CR1(lo), Ccr(7+)CX3CR1(int) (lymph migratory), and Cxcl(13+)CX3CR1(hi) (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 Cxcl73(+) CX3CR1(hi) 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(+)CX3CR1(int) 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.