title: IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases.
abstract: B lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has been associated primarily with interleukin 10 (IL-10) because B-cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens. Here we identify IL-35-producing B cells as key players in the negative regulation of immunity. Mice in which only B cells did not express IL-35 lost their ability to recover from the T-cell-mediated demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE). In contrast, these mice displayed a markedly improved resistance to infection with the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as shown by their superior containment of the bacterial growth and their prolonged survival after primary infection, and upon secondary challenge, compared to control mice. The increased immunity found in mice lacking IL-35 production by B cells was associated with a higher activation of macrophages and inflammatory T cells, as well as an increased function of B cells as antigen-presenting cells (APCs). During Salmonella infection, IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM(+)CD138(hi)TACI(+)CXCR4(+)CD1d(int)Tim1(int) plasma cells expressing the transcription factor Blimp1 (also known as Prdm1). During EAE, CD138(+) plasma cells were also the main source of B-cell-derived IL-35 and IL-10. Collectively, our data show the importance of IL-35-producing B cells in regulation of immunity and highlight IL-35 production by B cells as a potential therapeutic target for autoimmune and infectious diseases. This study reveals the central role of activated B cells, particularly plasma cells, and their production of cytokines in the regulation of immune responses in health and disease.
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Ping
authors.initials: P
authors.lastname: Shen
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Toralf
authors.initials: T
authors.lastname: Roch
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Vicky
authors.initials: V
authors.lastname: Lampropoulou
authors.affiliation: University of Edinburgh, Centre for Inflammation Research and Centre for Multiple Sclerosis Research, Queen's Medical Research Institute, Edinburgh, EH16 4TJ, United Kingdom.
authors.forename: Richard A
authors.initials: RA
authors.lastname: O'Connor
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Ulrik
authors.initials: U
authors.lastname: Stervbo
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Hilgenberg
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Ries
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Van Duc
authors.initials: VD
authors.lastname: Dang
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Yarúa
authors.initials: Y
authors.lastname: Jaimes
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.|Charité Universitätsmedizin Berlin, CC12, Dept. Medicine/Rheumatology and Clinical Immunology, 10117 Berlin, Germany.
authors.forename: Capucine
authors.initials: C
authors.lastname: Daridon
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, H3A2B4, Canada.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Virologie et Immunologie Moléculaires, INRA, 78352 Jouy-en-Josas, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Jouneau
authors.affiliation: Virologie et Immunologie Moléculaires, INRA, 78352 Jouy-en-Josas, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Boudinot
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Siska
authors.initials: S
authors.lastname: Wilantri
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Imme
authors.initials: I
authors.lastname: Sakwa
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, H3A2B4, Canada.
authors.forename: Yusei
authors.initials: Y
authors.lastname: Miyazaki
authors.affiliation: University of Edinburgh, Centre for Inflammation Research and Centre for Multiple Sclerosis Research, Queen's Medical Research Institute, Edinburgh, EH16 4TJ, United Kingdom.
authors.forename: Melanie D
authors.initials: MD
authors.lastname: Leech
authors.affiliation: University of Edinburgh, Centre for Inflammation Research and Centre for Multiple Sclerosis Research, Queen's Medical Research Institute, Edinburgh, EH16 4TJ, United Kingdom.
authors.forename: Rhoanne C
authors.initials: RC
authors.lastname: McPherson
authors.affiliation: Medical Clinic 1, Kussmaul Campus for Medical Research, University of Erlangen-Nürnberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.affiliation: Medical Clinic 1, Kussmaul Campus for Medical Research, University of Erlangen-Nürnberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Neurath
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Hoehlig
authors.affiliation: Institut für Klinische Neuroimmunologie Klinikum der Ludwig-Maximilians-Universität München, 81377 München, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Meinl
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Grützkau
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Grün
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Horn
authors.affiliation: Immunpathologie, Research Center ImmunoSciences, 12203 Berlin, Germany.
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.|Charité Universitätsmedizin Berlin, CC12, Dept. Medicine/Rheumatology and Clinical Immunology, 10117 Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dörner
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, H3A2B4, Canada.
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or
authors.affiliation: Max Planck Institute of Infection Biology, Department of Immunology, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Stefan H E
authors.initials: SHE
authors.lastname: Kaufmann
authors.affiliation: University of Edinburgh, Centre for Inflammation Research and Centre for Multiple Sclerosis Research, Queen's Medical Research Institute, Edinburgh, EH16 4TJ, United Kingdom.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Anderton
authors.affiliation: Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Fillatreau
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D019013:CD40 Antigens / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D006801:Humans; D007109:Immunity / Q000276:immunology*; D016753:Interleukin-10 / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D012480:Salmonella Infections / Q000276:immunology* / Q000382:microbiology; D013601:T-Lymphocytes / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D007378:Interleukins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C569375:interleukin-35, mouse; D016753:Interleukin-10