title: Interleukin-7 and Toll-like receptor 7 induce synergistic B cell and T cell activation.
abstract: OBJECTIVE
  To investigate the potential synergy of IL-7-driven T cell-dependent and TLR7-mediated B cell activation and to assess the additive effects of monocyte/macrophages in this respect.
  
  
  METHODS
  Isolated CD19 B cells and CD4 T cells from healthy donors were co-cultured with TLR7 agonist (TLR7A, Gardiquimod), IL-7, or their combination with or without CD14 monocytes/macrophages (T/B/mono; 1 : 1 : 0,1). Proliferation was measured using 3H-thymidine incorporation and Ki67 expression. Activation marker (CD19, HLA-DR, CD25) expression was measured by FACS analysis. Immunoglobulins were measured by ELISA and release of cytokines was measured by Luminex assay.
  
  
  RESULTS
  TLR7-induced B cell activation was not associated with T cell activation. IL-7-induced T cell activation alone and together with TLR7A synergistically increased numbers of both proliferating (Ki67+) B cells and T cells, which was further increased in the presence of monocytes/macrophages. This was associated by up regulation of activation markers on B cells and T cells. Additive or synergistic induction of production of immunoglobulins by TLR7 and IL-7 was associated by synergistic induction of T cell cytokines (IFNγ, IL-17A, IL-22), which was only evident in the presence of monocytes/macrophages.
  
  
  CONCLUSIONS
  IL-7-induced CD4 T cell activation and TLR7-induced B cell activation synergistically induce T helper cell cytokine and B cell immunoglobulin production, which is critically dependent on monocytes/macrophages. Our results indicate that previously described increased expression of IL-7 and TLR7 together with increased numbers of macrophages at sites of inflammation in autoimmune diseases like RA and pSS significantly contributes to enhanced lymphocyte activation.
authors.affiliation: Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Angela
authors.initials: A
authors.lastname: Bikker
authors.affiliation: Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Aike A
authors.initials: AA
authors.lastname: Kruize
authors.affiliation: Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Kim M G
authors.initials: KM
authors.lastname: van der Wurff-Jacobs
authors.affiliation: Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Rogier P
authors.initials: RP
authors.lastname: Peters
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
authors.forename: Marije
authors.initials: M
authors.lastname: Kleinjan
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Redegeld
authors.affiliation: Department of Pediatric Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Wilco
authors.initials: W
authors.lastname: de Jager
authors.affiliation: Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Floris P J G
authors.initials: FP
authors.lastname: Lafeber
authors.affiliation: Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Joël A G
authors.initials: JA
authors.lastname: van Roon
mesh_terms: D000634:Aminoquinolines / Q000276:immunology / Q000494:pharmacology; D018941:Antigens, CD19 / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000276:immunology / Q000494:pharmacology; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D007075:Immunoglobulin M / Q000276:immunology / Q000378:metabolism; D015851:Interleukin-7 / Q000276:immunology* / Q000494:pharmacology; D019394:Ki-67 Antigen / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000276:immunology* / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D018941:Antigens, CD19; D016207:Cytokines; D006684:HLA-DR Antigens; D007093:Imidazoles; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D015851:Interleukin-7; D019394:Ki-67 Antigen; D051199:Toll-Like Receptor 7; C546771:gardiquimod
references.citation: Arthritis Rheum. 2010 Apr;62(4):969-77
references.pmid: 20131250
references.citation: Arthritis Rheum. 2008 Jun;58(6):1619-29
references.pmid: 18512782
references.citation: Nat Rev Immunol. 2008 Aug;8(8):594-606
references.pmid: 18641647
references.citation: J Neuroimmunol. 2010 May;222(1-2):82-6
references.pmid: 20226540
references.citation: Nat Med. 2005 Jan;11(1):85-9
references.pmid: 15619631
references.citation: Arthritis Rheum. 2010 Sep;62(9):2716-25
references.pmid: 20499386
references.citation: J Exp Med. 2005 Nov 7;202(9):1171-7
references.pmid: 16260486
references.citation: Nat Rev Immunol. 2007 Feb;7(2):144-54
references.pmid: 17259970
references.citation: J Rheumatol. 1995 Aug;22(8):1581-5
references.pmid: 7473488
references.citation: Ann Rheum Dis. 2009 Mar;68(3):420-6
references.pmid: 18397959
references.citation: Trends Immunol. 2001 Oct;22(10):564-71
references.pmid: 11574281
references.citation: Arthritis Rheum. 2009 Sep;60(9):2595-605
references.pmid: 19714586
references.citation: Curr Pharm Des. 2012;18(16):2347-56
references.pmid: 22390698
references.citation: Immunol Rev. 2005 Feb;203:110-26
references.pmid: 15661025
references.citation: Nat Med. 2010 Feb;16(2):191-7
references.pmid: 20062065
references.citation: Immunity. 2006 Sep;25(3):429-40
references.pmid: 16973388
references.citation: J Immunol. 2005 Feb 15;174(4):2376-86
references.pmid: 15699174
references.citation: J Immunol. 2009 Oct 15;183(8):4833-7
references.pmid: 19801508
references.citation: Rheumatol Int. 1996;15(6):239-47
references.pmid: 8778952
references.citation: J Exp Med. 2003 Dec 15;198(12):1797-806
references.pmid: 14662907
references.citation: J Immunol. 2003 Aug 1;171(3):1556-63
references.pmid: 12874249
references.citation: J Rheumatol. 2007 May;34(5):1019-26
references.pmid: 17407216
references.citation: Ann Rheum Dis. 2003 Feb;62(2):113-9
references.pmid: 12525379
references.citation: Curr Opin Rheumatol. 2011 Nov;23(6):505-10
references.pmid: 21885976
references.citation: J Exp Med. 1998 Feb 2;187(3):389-402
references.pmid: 9449719
references.citation: Nat Rev Immunol. 2011 May;11(5):330-42
references.pmid: 21508983
references.citation: Mol Immunol. 2009 Apr;46(7):1278-88
references.pmid: 19157556
references.citation: World J Gastroenterol. 2008 Sep 7;14(33):5138-48
references.pmid: 18777590
references.citation: J Clin Invest. 1995 Jun;95(6):2945-53
references.pmid: 7769137
references.citation: Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010 Jun;109(6):844-50
references.pmid: 20399690
references.citation: Ann Rheum Dis. 2010 Dec;69(12):2137-44
references.pmid: 20679475
references.citation: J Autoimmun. 2010 Nov;35(3):212-8
references.pmid: 20685081
references.citation: J Autoimmun. 2012 Jun;38(4):304-14
references.pmid: 22341853
references.citation: Ann N Y Acad Sci. 2005 Dec;1062:242-51
references.pmid: 16461805
references.citation: J Mol Med (Berl). 2005 Oct;83(10):822-30
references.pmid: 16075257
references.citation: Autoimmunity. 2006 Feb;39(1):63-70
references.pmid: 16455583
references.citation: Clin Exp Immunol. 2007 Mar;147(3):497-503
references.pmid: 17302899
references.citation: Ann Rheum Dis. 2013 May;72(5):728-35
references.pmid: 22736090
references.citation: Clin Exp Immunol. 1998 Feb;111(2):457-62
references.pmid: 9486419
references.citation: Immunity. 2006 Sep;25(3):417-28
references.pmid: 16973389
references.citation: J Autoimmun. 2012 Aug;39(1-2):69-76
references.pmid: 22357449
references.citation: Ann Rheum Dis. 2012 Jun;71(6):1027-33
references.pmid: 22312161
references.citation: J Autoimmun. 2010 Jun;34(4):400-7
references.pmid: 19889514
references.citation: J Clin Immunol. 1997 Jul;17(4):282-92
references.pmid: 9258767
references.citation: Autoimmunity. 2010 Feb;43(1):76-83
references.pmid: 20014959
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5598-603
references.pmid: 15034168
references.citation: Eur J Immunol. 2008 Feb;38(2):400-9
references.pmid: 18228247
references.citation: Arthritis Rheum. 2005 Aug;52(8):2313-22
references.pmid: 16052591
references.citation: Rheumatology (Oxford). 2010 Nov;49(11):2084-9
references.pmid: 20693259
references.citation: Arthritis Rheum. 2008 Nov;58(11):3430-5
references.pmid: 18975340
references.citation: Arthritis Rheum. 2004 Dec;50(12):3856-65
references.pmid: 15593217
references.citation: Rheumatol Int. 1987;7(5):183-6
references.pmid: 3321379
references.citation: Rheumatology (Oxford). 2012 Jun;51(6):996-1005
references.pmid: 22302060
references.citation: Eur J Immunol. 2007 Dec;37(12):3582-6
references.pmid: 18034431
references.citation: Clin Immunol Immunopathol. 1997 Apr;83(1):41-4
references.pmid: 9073534
references.citation: J Immunol. 2005 Jun 1;174(11):6571-6
references.pmid: 15905493
references.citation: Arthritis Rheum. 2005 Jun;52(6):1700-10
references.pmid: 15934068
references.citation: Ann Rheum Dis. 2007 May;66(5):589-98
references.pmid: 17170049