RT Journal Article
SR Electronic
T1 Innate lymphoid cells regulate intestinal epithelial cell glycosylation
JF Science
JO Science
FD American Association for the Advancement of Science
SP 1254009
DO 10.1126/science.1254009
VO 345
IS 6202
A1 Goto, Yoshiyuki
A1 Obata, Takashi
A1 Kunisawa, Jun
A1 Sato, Shintaro
A1 Ivanov, Ivaylo I.
A1 Lamichhane, Aayam
A1 Takeyama, Natsumi
A1 Kamioka, Mariko
A1 Sakamoto, Mitsuo
A1 Matsuki, Takahiro
A1 Setoyama, Hiromi
A1 Imaoka, Akemi
A1 Uematsu, Satoshi
A1 Akira, Shizuo
A1 Domino, Steven E.
A1 Kulig, Paulina
A1 Becher, Burkhard
A1 Renauld, Jean-Christophe
A1 Sasakawa, Chihiro
A1 Umesaki, Yoshinori
A1 Benno, Yoshimi
A1 Kiyono, Hiroshi
YR 2014
UL http://science.sciencemag.org/content/345/6202/1254009.abstract
AB INTRODUCTIONThe combination of food intake and the resident gut microbiota exposes the gastrointestinal (GI) tract to numerous antigens. Intestinal epithelial cells (ECs) compose a physical barrier separating the internal organs from the gut microbiota and other pathogenic microorganisms entering the GI tract. Although anatomically contained, the gut microbiota is essential for developing appropriate host immunity. Thus, the mucosal immune system must simultaneously maintain homeostasis with the gut microbiota and protect against infection by pathogens. Maintenance of the gut microbiota requires epithelial cell-surface glycosylation, with fucose residues in particular. Epithelial fucosylation is mediated by the enzyme fucosyltransferase 2 (Fut2). Polymorphisms in the FUT2 gene are associated with the onset of multiple infectious and inflammatory diseases and metabolic syndrome in humans.ILC3s regulate epithelial glycosylation. Commensal bacteria, including segmented filamentous bactiera (SFB), induce IL-22 production by ILC3. LT is produced by ILC3 in a commensal bacteria–independent manner. ILC3-derived IL-22 and LT cooperatively induce the production of Fut2 and subsequent epithelial fucosylation, which protects the host against Salmonella typhimurium infection.RATIONALEDespite its importance, the mechanisms underlying epithelial fucosylation in the GI tract is not well understood. In particular, although commensals such as Bacteroides thetaiotaomicron induce epithelial fucosylation, how mucosal immune cells participate in this process is unknown. We used a combination of bacteriological, gnotobiological, and immunological techniques to elucidate the cellular and molecular basis of epithelial fucosylation by mucosal immune cells in mice, especially innate lymphoid cells (ILCs). To explore the role of ILCs in the induction and maintenance of epithelial fucosylation, we used genetically engineered mice lacking genes associated with the development and function of ILCs. To investigate the physiological functions of ILC-induced epithelial fucosylation, we used a Fut2-deficient mouse model of S. typhimurium infection.RESULTSThe induction and maintenance of Fut2 expression and subsequent epithelial fucosylation in the GI tract required type 3 ILCs (ILC3s) that express the transcription factor RORγtand the cytokines interleukin-22 (IL-22) and lymphotoxin (LT). Commensal bacteria, including segmented filamentous bacteria (SFB), induced fucosylation of intestinal columnar ECs and goblet cells. Expression of IL-22 by ILC3 required commensal bacteria, whereas LT was expressed in a commensal-independent manner. Ablation of IL-22 or LT in ILC3 resulted in a marked reduction in epithelial fucosylation, demonstrating that both cytokines are critical for the induction and regulation of epithelial fucosylation. Fucosylation of ECs in response to the intestinal pathogen S. typhimurium was also mediated by ILC3. Compared with control mice, Fut2-deficient mice were more susceptible to pathogenic inflammation as a result of S. typhimurium infection, suggesting that epithelial fucosylation contributes to host defense against S. typhimurium infection.CONCLUSIONWe demonstrate the critical role of the cytokines IL-22­– and/or LT-producing ILC3 in the induction and regulation of intestinal epithelial fucosylation. We also show that ILC3-mediated epithelial fucosylation protects the host from invasion of S. typhimurium into the intestine. Our results provide important details of the glycosylation system and homeostatic responses created by the trilateral ILC3–EC–commensal axis in the intestine. Modulation of mucosal immune cell–mediated epithelial glycosylation may provide novel targets for the treatment or prevention of infectious diseases in humans.Epithelial cells line the intestinal tract and help to keep the peace between our immune system and our trillions of gut microbes. Such peacekeeping requires glycosylated proteins (proteins with attached carbohydrate chains) present on the epithelial cell surface, but how glycosylation occurs is unclear. Goto et al. find that fucosylation (a type of glycosylation) of gut epithelial cells in mice requires gut microbes (see the Perspective by Hooper). This process also requires innate lymphoid cells there, which produce the cytokines interleukin-22 and lymphotoxin, presumably in response to microbial signals. These cytokines signal epithelial cells to add fucose to membrane proteins, which allows the détente between microbes and immune cells to continue.Science, this issue 10.1126/science.1254009; see also p. 1248Fucosylation of intestinal epithelial cells, catalyzed by fucosyltransferase 2 (Fut2), is a major glycosylation mechanism of host–microbiota symbiosis. Commensal bacteria induce epithelial fucosylation, and epithelial fucose is used as a dietary carbohydrate by many of these bacteria. However, the molecular and cellular mechanisms that regulate the induction of epithelial fucosylation are unknown. Here, we show that type 3 innate lymphoid cells (ILC3) induced intestinal epithelial Fut2 expression and fucosylation in mice. This induction required the cytokines interleukin-22 and lymphotoxin in a commensal bacteria–dependent and –independent manner, respectively. Disruption of intestinal fucosylation led to increased susceptibility to infection by Salmonella typhimurium. Our data reveal a role for ILC3 in shaping the gut microenvironment through the regulation of epithelial glycosylation.