title: Ecto-nucleoside triphosphate diphosphohydrolase 7 controls Th17 cell responses through regulation of luminal ATP in the small intestine.
abstract: Extracellular ATP is released from live cells in controlled conditions, as well as dying cells in inflammatory conditions, and, thereby, regulates T cell responses, including Th17 cell induction. The level of extracellular ATP is closely regulated by ATP hydrolyzing enzymes, such as ecto-nucleoside triphosphate diphosphohydrolases (ENTPDases). ENTPDase1/CD39, which is expressed in immune cells, was shown to regulate immune responses by downregulating the ATP level. In this study, we analyzed the immunomodulatory function of ENTPDase7, which is preferentially expressed in epithelial cells in the small intestine. The targeted deletion of Entpd7 encoding ENTPDase7 in mice resulted in increased ATP levels in the small intestinal lumen. The number of Th17 cells was selectively increased in the small intestinal lamina propria in Entpd7(-/-) mice. Th17 cells were decreased by oral administration of antibiotics or the ATP antagonist in Entpd7(-/-) mice, indicating that commensal microbiota-dependent ATP release mediates the enhanced Th17 cell development in the small intestinal lamina propria of Entpd7(-/-) mice. In accordance with the increased number of small intestinal Th17 cells, Entpd7(-/-) mice were resistant to oral infection with Citrobacter rodentium. Entpd7(-/-) mice suffered from severe experimental autoimmune encephalomyelitis, which was associated with increased numbers of CD4(+) T cells producing both IL-17 and IFN-γ. Taken together, these findings demonstrate that ENTPDase7 controls the luminal ATP level and, thereby, regulates Th17 cell development in the small intestine.
authors.affiliation: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kusu
authors.forename: Hisako
authors.initials: H
authors.lastname: Kayama
authors.forename: Makoto
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Seong Gyu
authors.initials: SG
authors.lastname: Jeon
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Ueda
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Goto
authors.forename: Ryu
authors.initials: R
authors.lastname: Okumura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Saiga
authors.forename: Takashi
authors.initials: T
authors.lastname: Kurakawa
authors.forename: Kayo
authors.initials: K
authors.lastname: Ikeda
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Maeda
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Nishimura
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Arima
authors.forename: Koji
authors.initials: K
authors.lastname: Atarashi
authors.forename: Kenya
authors.initials: K
authors.lastname: Honda
authors.forename: Masaaki
authors.initials: M
authors.lastname: Murakami
authors.forename: Jun
authors.initials: J
authors.lastname: Kunisawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyono
authors.forename: Meinoshin
authors.initials: M
authors.lastname: Okumura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D044082:Citrobacter rodentium / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D004756:Enterobacteriaceae Infections / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D007421:Intestine, Small / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D054892:Metagenome; D051379:Mice; D018345:Mice, Knockout; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000255:Adenosine Triphosphate; D011755:Pyrophosphatases; C021895:nucleoside triphosphate pyrophosphatase