学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 水島 昇, 東京大学教授 三宅 健介, 東京大学教授 松島 綱治, 東京大学教授 北村 俊雄, 東京大学准教授 新田 剛University of Tokyo(東京大学

Kamioka Mariko

神岡 真理子

UTokyo Repository

論文の内容の要旨 
 
論文題目 Critical role of host immune cells for the induction and regulation of Paneth cells 
（宿主免疫細胞によるパネート細胞の分化・機能調節機構の解明） 
 
 
 神岡 真理子  
 
The gastrointestinal tract is constantly exposed to numerous foreign antigens. Intestinal epithelial 
cell (IEC) layer acts as a first line of defense and is divided into villi and crypt regions. In the crypts, 
epithelial stem cells and Paneth cells are preferentially located. Paneth cells release granules containing a 
variety of antimicrobial peptides as a major part of the host innate immune system. α-defensin is most 
abundant and highly bactericidal peptide specifically produced by Paneth cells. Paneth cells also produce 
and secrete Delta-like 1/4, epidermal growth factor and Wnt to constitute the niche for epithelial stem cells. 
Defects of Paneth cells cause the disturbance of epithelial cell differentiation, dysbiosis and/or aggravation 
of gastrointestinal disorders. 
 
IECs create a co-habitation niche for commensal bacteria by using α(1,2)fucosylation, one of 
glycosylation system. α(1,2)fucosylation of IECs is regulated by two fucosyltransferases, Fut1 and Fut2. A 
previous study has shown that segmented filamentous bacteria induce Fut2 expression in villus epithelial 
cells. Interleukin 22 (IL-22) produced by type3 innate lymphoid cells is another stimulator for the induction 
of Fut2 in IECs. It has been also shown that α(1,2)fucose is expressed not only in columnar epithelial cells 
but also in crypts, where Paneth cells are preferentially localized. However, the mechanism and functional 
significance of α(1,2)fucosylation in Paneth cells has been unrevealed.       
 
In this study, I aimed to elucidate the mechanism underlying α(1,2)fucosylation in Paneth cells 
and the significance of α(1,2)fucosylation for Paneth cells development and function. Especially, I focused 
on Fut2-induced α(1,2)fucosylation in Paneth cells, because FUT2 nonsense polymorphisms are found to 
be related with Crohn’s disease. Further, there is a possibility that Fut2-induced α(1,2)fucosylation has 
important roles in the functions of Paneth cells for creating and maintaining healthy intestinal environment. 
My study was also aimed to understand the regulation mechanism of Fut2+Paneth cells by intestinal immune 
cells. Several previous studies have demonstrated that innate immune cells such as innate lymphoid cells 
regulate the IEC development and function. However, limited information is currently available for our 
understanding of whether intestinal immune cells regulate Paneth cell development and functions. In this 
study, I thus analyzed possible roles of innate and adaptive immune systems for the induction and regulation 
of Paneth cells, especially those of Fut2 harboring cells. 
 
By analyzing Fut1-deficient mice, Fut2-deficient mice and wild type mice, I found two subtypes 
of Paneth cells that are classified on the basis of their expression of Fut2. Fut2-positive (Fut2+) Paneth cells 
were preferentially located in ileum, whereas large portion of Fut2-negative (Fut2−) Paneth cells was 
located in duodenum. Since the preferential localization of Fut2+ Paneth cells in ileal crypts is correlated 
with the bacterial load of commensal microbiota (duodenum: 102–103 microorganisms, ileum: 107–108 
microorganisms), my results suggested that Fut2+ Paneth cells are committed to the eradication of luminal 
microbiota by producing antimicrobial peptides. Indeed, the production of antimicrobial peptides was 
higher in ileal Paneth cells which were mainly composed of Fut2+ Paneth cells than duodenal Paneth cells. 
I further found a possibility that Fut2− Paneth cells have higher ability to constitute the niche for epithelial 
stem cells when compared with Fut2+ Paneth cells. 
 
I next examined possible molecular mechanisms involved in the induction of Fut2+ Paneth cell 
development. I found that IL-22 signaling, known as a part of innate immune system, induced the 
development of Fut2+ but not Fut2−, Paneth cells with mature granules containing α-defensin. I further 
analyzed ileal Paneth cells in Rag1-deficient mice which lack both T and B cells to elucidate the 
involvement of adaptive immune system for governing Fut2+ Paneth cell. I found a possibility that the 
adaptive immune system is involved in the granule release from Fut2+ Paneth cells. 
 
In summary, Paneth cells can be separated into two subsets based on their utilization of Fut2. 
Fut2+ Paneth cells are preferentially located in ileum, whereas Fut2− Paneth cells are in duodenum. My 
current study has indicated a possibility that Fut2+ and Fut2− Paneth cells have critical roles in host defense 
and constitution of stem cells niche respectively. It has been also suggested that both innate and adaptive 
immune systems are essential for Fut2+ Paneth cell development and functional expression, respectively. 
Further molecular and cellular analyses of Fut2+ and Fut2− Paneth cells will reveal how Paneth cells 
contribute to the creation of healthy gastrointestinal environment. 


宿主免疫細胞によるパネート細胞の分化・機能調節機構の解明

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宿主免疫細胞によるパネート細胞の分化・機能調節機構の解明

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