Saravana Kanagavelu1, Claudia Flores2, Shinichiro Hagiwara2, Jose Ruiz2, Jinhee Hyun3, Ei E Cho2, Frank Sun2, Laura Romero4, David Q Shih2, Masayuki Fukata5. 1. 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. 2. Division of Gastroenterology, Department of Medicine, F. Widjaja Foundation, Inflammatory Bowel and Immunology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. 3. Department of Cell Biology, University of Miami Miller School of Medicine, Miami, Florida, USA. 4. Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. 5. 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.
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. METHOD: 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 with Y. enterocolitica. Y. enterocolitica-specific CD4+CXCR5+ T cells were generated in vitro by co-culturing peritoneal macrophages with splenic naïve T cells in the presence of Y. enterocolitica lysate. WT and TrifLPS2 mice received CD4+CXCR5+ T cells isolated either from Y. enterocolitica-primed WT mice or generated in vitro. These mice were infected with Y. enterocolitica and 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 TrifLPS2 mice compared to WT mice. After infection, the proportion of plasma cells also became higher in the PPs of TrifLPS2 mice compared to WT mice. Corresponding increase of Y. enterocolitica-specific stool IgA but not serum IgG was found in TrifLPS2 mice compared to WT mice. Both in vivo isolated and in vitro generated CD4+CXCR5+ T cells induced protective immunity against Y. enterocolitica infection. CONCLUSION: 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.
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. METHOD: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 with Y. enterocolitica. Y. enterocolitica-specific CD4+CXCR5+ T cells were generated in vitro by co-culturing peritoneal macrophages with splenic naïve T cells in the presence of Y. enterocolitica lysate. WT and TrifLPS2 mice received CD4+CXCR5+ T cells isolated either from Y. enterocolitica-primed WT mice or generated in vitro. These mice were infected with Y. enterocolitica and 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 TrifLPS2 mice compared to WT mice. After infection, the proportion of plasma cells also became higher in the PPs of TrifLPS2 mice compared to WT mice. Corresponding increase of Y. enterocolitica-specific stool IgA but not serum IgG was found in TrifLPS2 mice compared to WT mice. Both in vivo isolated and in vitro generated CD4+CXCR5+ T cells induced protective immunity against Y. enterocolitica infection. CONCLUSION: 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.
Entities:
Keywords:
B cells; Bacterial infection; Enterocolitis; Innate immunity; Intestine; Mucosal vaccine; Plasma cells; T follicular helper cells
Authors: Sachin Gupta; Emily S Clark; James M Termini; Justin Boucher; Saravana Kanagavelu; Celia C LeBranche; Sakhi Abraham; David C Montefiori; Wasif N Khan; Geoffrey W Stone Journal: J Virol Date: 2015-01-28 Impact factor: 5.103
Authors: Robert Belshe; Min-Shi Lee; Robert E Walker; Jeffrey Stoddard; Paul M Mendelman Journal: Expert Rev Vaccines Date: 2004-12 Impact factor: 5.217
Authors: Limin Shang; Masayuki Fukata; Nanthakumar Thirunarayanan; Andrea P Martin; Paul Arnaboldi; David Maussang; Cecilia Berin; Jay C Unkeless; Lloyd Mayer; Maria T Abreu; Sergio A Lira Journal: Gastroenterology Date: 2008-04-22 Impact factor: 22.682
Authors: John Sotolongo; Cecilia España; Andrea Echeverry; David Siefker; Norman Altman; Julia Zaias; Rebeca Santaolalla; Jose Ruiz; Kurt Schesser; Becky Adkins; Masayuki Fukata Journal: J Exp Med Date: 2011-11-28 Impact factor: 14.307
Authors: M Hahne; T Kataoka; M Schröter; K Hofmann; M Irmler; J L Bodmer; P Schneider; T Bornand; N Holler; L E French; B Sordat; D Rimoldi; J Tschopp Journal: J Exp Med Date: 1998-09-21 Impact factor: 14.307