title: TLR-2-activated B cells suppress Helicobacter-induced preneoplastic gastric immunopathology by inducing T regulatory-1 cells.
abstract: B cells regulate autoimmune pathologies and chronic inflammatory conditions such as autoimmune encephalomyelitis and inflammatory bowel disease. The potential counterregulatory role of B cells in balancing pathogen-specific immune responses and the associated immunopathology is less well understood owing to the lack of appropriate persistent infection models. In this paper, we show that B cells have the ability to negatively regulate adaptive immune responses to bacterial pathogens. Using mouse models of infection with Helicobacter felis, a close relative of the human gastrointestinal pathogen H. pylori, we found that B cells activated by Helicobacter TLR-2 ligands induce IL-10-producing CD4(+)CD25(+) T regulatory-1 (Tr-1)-like cells in vitro and in vivo. Tr-1 conversion depends on TCR signaling and a direct T-/B-interaction through CD40/CD40L and CD80/CD28. B cell-induced Tr-1 cells acquire suppressive activity in vitro and suppress excessive gastric Helicobacter-associated immunopathology in vivo. Adoptive cotransfer of MyD88-proficient B cells and Tr-1 cells restores a normal gastric mucosal architecture in MyD88(-/-) and IL-10(-/-) mice in a manner that depends on T cellular, but not B cellular, IL-10 production. Our findings describe a novel mechanism of B cell-dependent Tr-1 cell generation and function in a clinically relevant disease model. In conclusion, we demonstrate that the B cell/Tr-1 cell axis is essential for balancing the control of Helicobacter infection with the prevention of excessive Th1-driven gastric immunopathology, promoting gastric mucosal homeostasis on the one hand and facilitating Helicobacter persistence on the other.
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, Zürich 8057, Switzerland.
authors.forename: Ayca
authors.initials: A
authors.lastname: Sayi
authors.forename: Esther
authors.initials: E
authors.lastname: Kohler
authors.forename: Isabella M
authors.initials: IM
authors.lastname: Toller
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.forename: Axel
authors.initials: A
authors.lastname: Roers
authors.forename: Anne
authors.initials: A
authors.lastname: Müller
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D016481:Helicobacter Infections / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D044922:Helicobacter felis / Q000276:immunology; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D011230:Precancerous Conditions / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D013274:Stomach Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*
chemical_list: D008024:Ligands; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2