Helicobacter-stimulated IL-10-producing B cells suppress differentiation of lipopolysaccharide/Helicobacter felis-activated stimulatory dendritic cells

Regulatory B cells (Bregs) produce antiinflammatory cytokines and inhibits proinflammatory response. Recently,immunosuppressive roles of Bregs in the effector functions of dendritic cells (DCs) were demonstrated. However, cross talk betweenBregs and DCs in Helicobacter infection remains unknown. Here, we showed that direct stimulation of bone marrow-derived DCs (BMDCs) with Helicobacter felis (H. felis) antigen upregulates their CD86 surface expression and causes the production of interleukin-6(IL-6), tumor necrosis factor alpha (TNF-α), interleukin-12 (IL-12), and interleukin-10 (IL-10). Furthermore, prestimulation of DCswith supernatants derived from both Helicobacter-stimulated IL-10– B (Hfstim-IL-10– B) or IL-10+ B (Hfstim-IL-10+) cells suppresses thesecretion of TNF-α and IL-6, but does not affect the expression of CD86 and secretion of IL-12 by lipopolysaccharide (LPS) or H. felisactivated BM-DCs. Remarkably, soluble factors secreted by Hfstim-IL-10– B cells, but not by Hfstim-IL-10+ B cells, suppress the secretionof IL-10 by BM-DCs upon subsequent LPS stimulation. In contrast, prestimulation with BM-DCs with supernatants of Hfstim-IL-10+ Bcells before H. felis antigen stimulation induces significantly their IL-10 production. Collectively, our data indicated that prestimulationwith soluble factors secreted by Hfstim-IL-10+ B cells, DCs exhibit a tolerogenic phenotype in response to LPS or Helicobacter antigen bysecreting high levels of IL-10, but decreased levels of IL-6 and TNF-α.

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Adnan E, Matsumoto T, Ishizaki J, Onishi S, Suemori K et al. (2016). Human tolerogenic dendritic cells generated with protein kinase C inhibitor are optimal for functional regulatory T cell induction - a comparative study. Clinical Immunology 173: 96- 108. doi: 10.1016/j.clim.2016.09.007
Banchereau J, Briere F, Caux C, Davoust J, Lebecque S et al. (2000). Immunobiology of dendritic cells. Annual Review of Immunology 18: 767-811. doi:10.1146/annurev. immunol.18.1.767
Baumgart DC, Metzke D, Guckelberger O, Pascher A, Grotzinger C et al. (2011). Aberrant plasmacytoid dendritic cell distribution and function in patients with Crohn’s disease and ulcerative colitis. Clinical and Experimental Immunology 166 (1): 46-54. doi: 10.1111/j.1365-2249.2011.04439.x
Bettelli E, Carrier Y, Gao W, Korn T, Strom TB et al. (2006). Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature 441 (7090): 235-238. doi: 10.1038/nature04753
Carter NA, Rosser EC, Mauri C (2012). Interleukin-10 produced by B cells is crucial for the suppression of Th17/Th1 responses, induction of T regulatory type 1 cells and reduction of collagen-induced arthritis. Arthritis Research and Therapy 14 (1): R32. doi: 10.1186/ar3736
Carter NA, Vasconcellos R, Rosser EC, Tulone C, Munoz-Suano A et al. (2011). Mice lacking endogenous IL-10-producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells. Journal of Immunology 186 (10): 5569- 5579. doi: 10.4049/jimmunol.1100284
Drakes ML, Czinn SJ, Blanchard TG (2006). Regulation of murine dendritic cell immune responses by Helicobacter felis antigen. Infection and Immunity 74 (8): 4624-4633. doi: 10.1128/ IAI.00289-06
Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM (2002). B cells regulate autoimmunity by provision of IL-10. Nature Immunology 3 (10): 944-950. doi: 10.1038/ni833
Fogel-Petrovic M, Long JA, Misso NL, Foster PS, Bhoola KD et al. (2007). Physiological concentrations of transforming growth factor beta1 selectively inhibit human dendritic cell function. International Immunopharmacology 7 (14): 1924-1933. doi: 10.1016/j.intimp.2007.07.003
Hafsi N, Voland P, Schwendy S, Rad R, Reindl W et al. (2004). Human dendritic cells respond to Helicobacter pylori, promoting NK cell and Th1-effector responses in vitro. Journal of Immunology 173 (2): 1249-1257. doi: 10.4049/jimmunol.173.2.1249
Hoces de la Guardia A, Staedel C, Kaafarany I, Clement A, Roubaud Baudron C et al. (2013). Inflammatory cytokine and microRNA responses of primary human dendritic cells cultured with Helicobacter pylori strains. Frontiers in Microbiology 4: 236. doi: 10.3389/fmicb.2013.00236
Horvath DJ Jr, Washington MK, Cope VA, Algood HM (2012). IL-23 contributes to control of chronic Helicobacter pyloriinfection and the development of T helper responses in a mouse model. Frontiers in Immunology 3: 56. doi: 10.3389/fimmu.2012.00056
Jiang HR, Muckersie E, Robertson M, Xu H, Liversidge J et al. (2002). Secretion of interleukin-10 or interleukin-12 by LPSactivated dendritic cells is critically dependent on time of stimulus relative to initiation of purified DC culture. Journal of Leukocyte Biology 72 (5): 978-985.
Käbisch R, Mejías-Luque R, Gerhard M, Prinz C (2014). Involvement of Toll-like receptors on Helicobacter pylori-induced immunity. PLoS One 9 (8): e104804. doi: 10.1371/journal.pone.0104804
Käbisch R, Semper RP, Wüstner S, Gerhard M, Mejías-Luque R (2016). Helicobacter pylori γ-glutamyltranspeptidase induces tolerogenic human dendritic cells by activation of glutamate receptors. Journal of Immunology 196 (10): 4246-4252. doi: 10.4049/jimmunol.1501062
Kao JY, Rathinavelu S, Eaton KA, Bai L, Zavros Y et al. (2006). Helicobacter pylori-secreted factors inhibit dendritic cell IL-12 secretion: a mechanism of ineffective host defense. American Journal of Physiology-Gastrointestinal and Liver Physiology 291 (1): G73-G81. doi: 10.1152/ajpgi.00139.2005
Kao JY, Zhang M, Miller MJ, Mills JC, Wang B et al. (2010). Helicobacter pylori immune escape is mediated by dendritic cell-induced Treg skewing and Th17 suppression in mice. Gastroenterology 138 (3): 1046-1054. doi: 10.1053/j.gastro.2009.11.043
Li X, Tan J, Zhang F, Xue Q, Wang N et al. (2019). H.pyloriinfection alleviates acute and chronic colitis with the expansion of regulatory B cells in mice. Inflammation 42 (5): 1611-1621. doi: 10.1007/s10753-019-01022-0
Lowes MA, Chamian F, Abello MV, Fuentes-Duculan J, Lin SL et al. (2005). Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a). Proceedings of the National Academy of Sciences of the United States of America 102 (52): 19057-19062. doi: 10.1073/pnas.0509736102
Maddur MS, Kaveri SV, Bayry J (2012). Regulation of human dendritic cells by B cells depends on the signals they receive. Blood 119 (16): 3863-3864. doi: 10.1182/blood-2012-02-408948
Maerz JK, Trostel C, Lange A, Parusel R, Michaelis L et al. (2020). Bacterial immunogenicity is critical for the induction of regulatory B cells in suppressing inflammatory immune responses. Frontiers in Immunology 10: 3093-3093. doi: 10.3389/fimmu.2019.03093
Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC et al. (2006). Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441 (7090): 231- 234. doi: 10.1038/nature04754
Matheu MP, Sen D, Cahalan MD, Parker I (2008). Generation of bone marrow derived murine dendritic cells for use in 2-photon imaging. Journal of Visualized Experiments (17): doi: 10.3791/773
Matsumoto M, Baba A, Yokota T, Nishikawa H, Ohkawa Y et al. (2014). Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. Immunity 41 (6): 1040-1051. doi: 10.1016/j.immuni.2014.10.016
Mauri C, Gray D, Mushtaq N, Londei M (2003). Prevention of arthritis by interleukin 10-producing B cells. Journal of Experimental Medicine 197 (4): 489-501. doi: 10.1084/jem.20021293
Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg RS, Bhan AK (2002). Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity 16 (2): 219-230. doi: 10.1016/ s1074-7613(02)00274-1
Morva A, Lemoine S, Achour A, Pers JO, Youinou P et al. (2012). Maturation and function of human dendritic cells are regulated by B lymphocytes. Blood 119 (1): 106-114. doi: 10.1182/ blood-2011-06-360768
Mou HB, Lin MF, Cen H, Yu J, Meng XJ (2004). TGF-beta1 treated murine dendritic cells are maturation resistant and down-regulate Toll-like receptor 4 expression. Journal of Zhejiang University Science 5 (10): 1239-1244. doi: 10.1631/ jzus.2004.1239
Moyat M, Velin D (2014). Immune responses to Helicobacter pylori infection. World Journal of Gastroenterology 20 (19): 5583- 5593. doi: 10.3748/wjg.v20.i19.5583
Oertli M, Sundquist M, Hitzler I, Engler DB, Arnold IC et al. (2012). DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection. Journal of Clinical Investigation 122 (3): 1082- 1096. doi: 10.1172/JCI61029
Oertli M, Noben M, Engler DB, Semper RP, Reuter S et al. (2013). Helicobacter pylori gamma-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance. Proceedings of the National Academy of Sciences of the United States of America 110 (8): 3047-3052. doi: 10.1073/ pnas.1211248110
Peek RMJr., Fiske C, Wilson KT (2010). Role of innate immunity in Helicobacter pylori-induced gastric malignancy. Physiological Reviews 90 (3): 831-858. doi: 10.1152/physrev.00039.2009
Rizzuti D, Ang M, Sokollik C, Wu T, Abdullah M et al. (2015). Helicobacter pylori inhibits dendritic cell maturation via interleukin-10-mediated activation of the signal transducer and activator of transcription 3 pathway. Journal of Innate Immunity 7 (2): 199-211. doi: 10.1159/000368232
Ronet C, Hauyon-La Torre Y, Revaz-Breton M, Mastelic B, Tacchini-Cottier F et al. (2010). Regulatory B cells shape the development of Th2 immune responses in BALB/c mice infected with Leishmania major through IL-10 production. Journal of Immunology 184 (2): 886-894. doi: 10.4049/ jimmunol.0901114
Rutella S, Danese S, Leone G (2006). Tolerogenic dendritic cells: cytokine modulation comes of age. Blood 108 (5): 1435-1440. doi: 10.1182/blood-2006-03-006403
Said SS, Barut GT, Mansur N, Korkmaz A, Sayi-Yazgan A (2018). Bacterially activated B-cells drive T cell differentiation towards Tr1 through PD-1/PD-L1 expression. Molecular Immunology 96: 48-60. doi: 10.1016/j.molimm.2018.02.010
Sayi A, Kohler E, Hitzler I, Arnold I, Schwendener R et al. (2009). The CD4+ T cell-mediated IFN-gamma response to Helicobacter infection is essential for clearance and determines gastric cancer risk. Journal of Immunology 182 (11): 7085-7101. doi: 10.4049/jimmunol.0803293
Sayi A, Kohler E, Toller IM, Flavell RA, Muller W et al. (2011). TLR2-activated B cells suppress Helicobacter-induced preneoplastic gastric immunopathology by inducing T regulatory-1 cells. Journal of Immunology 186 (2): 878-890. doi: 10.4049/ jimmunol.1002269
Sun CM, Deriaud E, Leclerc C, Lo-Man R (2005). Upon TLR9 signaling, CD5+ B cells control the IL-12-dependent Th1- priming capacity of neonatal DCs. Immunity 22 (4): 467-477. doi: 10.1016/j.immuni.2005.02.008
Takenaka MC, Quintana FJ (2017). Tolerogenic dendritic cells. Seminars in Immunopathology 39 (2): 113-120. doi: 10.1007/ s00281-016-0587-8
Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006). TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17- producing T cells. Immunity 24 (2): 179-189. doi: 10.1016/j. immuni.2006.01.001
Wolf SD, Dittel BN, Hardardottir F, Janeway CA Jr. (1996). Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. Journal of Experimental Medicine 184 (6): 2271-2278. doi: 10.1084/jem.184.6.2271
Zhang M, Liu M, Luther J, Kao JY (2010). Helicobacter pylori directs tolerogenic programming of dendritic cells. Gut Microbes 1 (5): 325-329. doi: 10.4161/gmic.1.5.13052
Zhang X, Deriaud E, Jiao X, Braun D, Leclerc C et al. (2007). Type I interferons protect neonates from acute inflammation through interleukin 10-producing B cells. Journal of Experimental Medicine 204 (5): 1107-1118. doi: 10.1084/jem.20062013