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Studies on the roles of C-type lectin receptors in the homeostasis of the immune system

Han Wei 東京理科大学 DOI:info:doi/10.20604/00003625

2021.06.09

概要

Part I Functional roles of Clec12B in colon tumors and colitis
Among the CLRs (C-type lectin receptors) mapped in the Dectin-1 cluster, Clec12B (Ctype lectin domain family 12 member B) is poorly understood among other CLRs. Clec12B is expressed on dendritic cells and macrophages. However, the ligands of Clec12B still remain to be elucidated. Previously, Dectin-1, one of CLRs, is suggested to be involved in the development of colitis and colon tumors by regulating intestinal commensal microbiota. But the functional roles of Clec12B are still unclear. In this study, I showed that Clec12B can alleviate the development of colitis and colon tumors. Clec12b–/– mice were more sensitive to DSS-induced colitis and AOM-DSS induced colon tumors. Data showed that microbiota from Clec12b–/– mice can aggravate colitis. Using germ-free mice and 16S rRNA sequencing, I have identified that the population of A.muciniphila was greatly reduced in Clec12b–/–mice, which can alleviate intestinal inflammation. Furthermore, I found that intestinal mucin (MUC2) was decreased in Clec12b–/– mice compared with WT mice. Since A. muciniphila is reported to utilize intestinal mucin as the only carbon source, it is possible that A. muciniphila growth was suppressed because of the deficiency of MUC2. Taken together, these observations suggest that Clec12B plays an important role in regulating immune responses of the colon by modifying gut microbiota.

Part II OVA-induced airway inflammation is ameliorated in Dectin-1–deficient mice, in which pulmonary Treg cells are expanded through modification of intestinal commensal bacteria
Dectin-1 (gene symbol: Clec7a) is one of the best known CLRs which mainly expressed in Macrophages and Dendritic cells. Tang et al. reported recently that Dectin-1 is also important for the homeostasis of the intestinal immune system by controlling regulatory T (Treg) cell differentiation through regulation of intestinal microbiota. However, it is not clear whether intestinal immune conditions affect immune responses in other organs. I examined the effects of Dectin-1 deficiency on allergic airway inflammation (AAI). OVA-induced AAI was attenuated in Clec7a–/– mice. Treatment with antibiotics, but not an antifungal agent, decreased the abundance of intestinal Treg cells and aggravated the symptoms of AAI in Clec7a–/– mice. Transplantation of gut microbiota from Clec7a–/– mice into antibiotic-treated hosts increased the abundance of intestinal Treg cells and ameliorated AAI. Over-colonization by Lactobacillus murinus, a Dectin-1 signaling regulated commensal bacterium, also promoted expansion of Treg cells in the colon and suppressed lung inflammation. Depletion of Treg cells with anti-CD25 antibody eliminated the phenotypic differences between WT and Clec7a–/– mice in OVA-induced AAI. These observations suggest that inhibition of Dectin-1 signaling ameliorates AAI by increasing the abundance of Treg cells in lungs through modification of intestinal commensal bacteria, suggesting a role for commensal microbiota in regulating inflammation in organs other than the intestine.

Thus, my studies suggest that both Dectin-1 and Clec12B are important for the intestinal immune homeostasis by regulating microbiota composition in the intestine.

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