title: TIR-Domain-Containing Adapter-Inducing Interferon-β(TRIF) Regulates CXCR5+ T helper Cells in the Intestine.
abstract: OBJECTIVE
  Establishing an effective humoral immunity is an important host defense mechanism in intestinal mucosa. T follicular helper (Tfh) cells are a spectrum of CXCR5 expressing T helper cells that induce antigen-specific B cell differentiation. Because the differentiation of T helper cells is largely regulated by innate immunity, we addressed whether TRIF signaling regulates Tfh cell differentiation and its ability to trigger humoral immune responses in the intestine.
  
  
  METHODS
  CD4+CXCR5+T cells, B cells, and plasma cells in the Peyer's patches (PPs) of WT and TRIF-deficient (TrifLPS2) mice were analyzed by flow cytometry at the baseline, 9 days post primary infection, and 7 days post-secondary infection withY. enterocolitica.Y. enterocolitica-specific CD4+CXCR5+T cells were generatedin vitroby co-culturing peritoneal macrophages with splenic naïve T cells in the presence ofY. enterocoliticalysate. WT and TrifLPS2mice received CD4+CXCR5+T cells isolated either fromY. enterocolitica-primed WT mice or generatedin vitro. These mice were infected withY. enterocoliticaand followed up to 4 weeks.Y. enterocolitica-specific IgA and IgG were measured in stool and serum samples, respectively.
  
  
  RESULTS
  At baseline, CD4+CXCR5+T cell proportion was higher but the proportion of B cells and plasma cells was lower in the PPs of TrifLPS2mice compared to WT mice. After infection, the proportion of plasma cells also became higher in the PPs of TrifLPS2mice compared to WT mice. Corresponding increase ofY. enterocolitica-specific stool IgA but not serum IgG was found in TrifLPS2mice compared to WT mice. Bothin vivoisolated andin vitrogenerated CD4+CXCR5+T cells induced protective immunity againstY. enterocoliticainfection.
  
  
  CONCLUSIONS
  Our results reveal a novel role of TRIF in the regulation of humoral immunity in the intestine that can be utilized as a basis for a unique vaccine strategy.
authors.affiliation: Division of Gastroenterology, Department of Medicine, F. Widjaja Foundation, Inflammatory Bowel and Immunology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA; Division of Infectious Diseases and Immunology, Department of Biomedical Science, Medicine and Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Saravana
authors.initials: S
authors.lastname: Kanagavelu
authors.affiliation: Division of Gastroenterology, Department of Medicine, F. Widjaja Foundation, Inflammatory Bowel and Immunology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Flores
authors.affiliation: Division of Gastroenterology, Department of Medicine, F. Widjaja Foundation, Inflammatory Bowel and Immunology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Hagiwara
authors.affiliation: Division of Gastroenterology, Department of Medicine, F. Widjaja Foundation, Inflammatory Bowel and Immunology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Ruiz
authors.affiliation: Department of Cell Biology, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Jinhee
authors.initials: J
authors.lastname: Hyun
authors.affiliation: Division of Gastroenterology, Department of Medicine, F. Widjaja Foundation, Inflammatory Bowel and Immunology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Ei E
authors.initials: EE
authors.lastname: Cho
authors.affiliation: Division of Gastroenterology, Department of Medicine, F. Widjaja Foundation, Inflammatory Bowel and Immunology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Romero
authors.affiliation: Division of Gastroenterology, Department of Medicine, F. Widjaja Foundation, Inflammatory Bowel and Immunology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: David Q
authors.initials: DQ
authors.lastname: Shih
authors.affiliation: Division of Gastroenterology, Department of Medicine, F. Widjaja Foundation, Inflammatory Bowel and Immunology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA; Department of Cell Biology, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fukata
keywords: B cells; Bacterial infection; Enterocolitis; Innate immunity; Intestine; Mucosal vaccine; Plasma cells; T follicular helper cells