Publication Date:
2014-02-28
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260166/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260166/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shen, Ping -- Roch, Toralf -- Lampropoulou, Vicky -- O'Connor, Richard A -- Stervbo, Ulrik -- Hilgenberg, Ellen -- Ries, Stefanie -- Dang, Van Duc -- Jaimes, Yarua -- Daridon, Capucine -- Li, Rui -- Jouneau, Luc -- Boudinot, Pierre -- Wilantri, Siska -- Sakwa, Imme -- Miyazaki, Yusei -- Leech, Melanie D -- McPherson, Rhoanne C -- Wirtz, Stefan -- Neurath, Markus -- Hoehlig, Kai -- Meinl, Edgar -- Grutzkau, Andreas -- Grun, Joachim R -- Horn, Katharina -- Kuhl, Anja A -- Dorner, Thomas -- Bar-Or, Amit -- Kaufmann, Stefan H E -- Anderton, Stephen M -- Fillatreau, Simon -- 087833/Wellcome Trust/United Kingdom -- 095831/Wellcome Trust/United Kingdom -- G0801924/Medical Research Council/United Kingdom -- G0901697/Medical Research Council/United Kingdom -- G1100084/Medical Research Council/United Kingdom -- Canadian Institutes of Health Research/Canada -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2014 Mar 20;507(7492):366-70. doi: 10.1038/nature12979. Epub 2014 Feb 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Chariteplatz 1, 10117 Berlin, Germany [2]. ; 1] Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Chariteplatz 1, 10117 Berlin, Germany [2] Institute of Biomaterial Science, Helmholtz-Zentrum Geesthacht, Centre for Materials and Coastal Research, Kantstrasse 55, 14513 Teltow, Germany. [3]. ; Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Chariteplatz 1, 10117 Berlin, Germany. ; University of Edinburgh, Centre for Inflammation Research and Centre for Multiple Sclerosis Research, Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK. ; 1] Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Chariteplatz 1, 10117 Berlin, Germany [2] Charite Universitatsmedizin Berlin, CC12, Department of Medicine/Rheumatology and Clinical Immunology, 10117 Berlin, Germany. ; Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec H3A2B4, Canada. ; Virologie et Immunologie Moleculaires, INRA, 78352 Jouy-en-Josas, France. ; Medical Clinic 1, Kussmaul Campus for Medical Research, University of Erlangen-Nurnberg, 91054 Erlangen, Germany. ; Institut fur Klinische Neuroimmunologie Klinikum der Ludwig-Maximilians-Universitat Munchen, 81377 Munchen, Germany. ; Immunpathologie, Research Center ImmunoSciences, 12203 Berlin, Germany. ; Max Planck Institute of Infection Biology, Department of Immunology, Chariteplatz 1, 10117 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24572363" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antigen-Presenting Cells/immunology/metabolism
;
Antigens, CD40/immunology
;
B-Lymphocytes/*immunology/*metabolism/secretion
;
Encephalomyelitis, Autoimmune, Experimental/*immunology
;
Female
;
Humans
;
Immunity/*immunology
;
Interleukin-10/metabolism
;
Interleukins/immunology/*metabolism/secretion
;
Lymphocyte Activation
;
Macrophages/cytology/immunology
;
Male
;
Mice
;
Plasma Cells/immunology/metabolism
;
Salmonella Infections/*immunology/microbiology
;
T-Lymphocytes/immunology
;
Toll-Like Receptor 4/immunology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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