title: Ligation of CD11c during vaccination promotes germinal centre induction and robust humoral responses without adjuvant.
abstract: In this study, we investigated the mouse dendritic cell (DC) receptor, complement receptor 4 (CR4; CD11c/CD18), as an immunotarget for triggering humoral immunity. Comparison of antibody titres generated against a panel of 13 anti-antigen-presenting cell receptor monoclonal antibodies, with or without conjugated ovalbumin (OVA), revealed uniquely rapid and robust responses following CR4 targeting, with antibody titres approaching 1 : 100 000 7 days after a single dose of antigen. Furthermore, using just 100 ng OVA conjugated to anti-CD11c Fab', we generated anti-OVA titres greater than those produced by a 100-fold higher dose of OVA in complete Freund's adjuvant at day 28. These anti-OVA antibody titres were sustained and could be boosted further with targeted OVA on day 21. Investigations to explain this vaccine potency showed that, in addition to targeting splenic DC, anti-CDl1c antibodies delivered a powerful adjuvant effect and could boost humoral immunity against OVA even when the OVA was targeted to other molecules on DC, such as major histocompatibility complex class II, CD11a and CD11b. However, interestingly, this adjuvant effect was lost if OVA was targeted to other cells such as B cells via CD21 or CD19. The adjuvant effect was mediated through a marked enhancement of both germinal centre and extrafollicular plasma cell formation in responding spleens. These results demonstrate that anti-CD11c monoclonal antibody can both target antigen and act as a powerful adjuvant for rapid and sustained antibody responses. They also point to an interesting role for CR4 on DC in triggering B cells during humoral immunity.
authors.affiliation: Tenovus Research Laboratory, Cancer Sciences Division, Southampton University School of Medicine, General Hospital, Southampton, UK.
authors.forename: Ann L
authors.initials: AL
authors.lastname: White
authors.forename: Alison L
authors.initials: AL
authors.lastname: Tutt
authors.forename: Sonya
authors.initials: S
authors.lastname: James
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Wilkinson
authors.forename: Fernanda V V
authors.initials: FV
authors.lastname: Castro
authors.forename: Sandra V
authors.initials: SV
authors.lastname: Dixon
authors.forename: Jessica
authors.initials: J
authors.lastname: Hitchcock
authors.forename: Mahmood
authors.initials: M
authors.lastname: Khan
authors.forename: Aymen
authors.initials: A
authors.lastname: Al-Shamkhani
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cunningham
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Glennie
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology*; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology; D039521:CD11c Antigen / Q000276:immunology* / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology; D018858:Germinal Center / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D039521:CD11c Antigen; D010047:Ovalbumin
references.citation: Annu Rev Immunol. 2003;21:685-711
references.pmid: 12615891
references.citation: J Immunol. 1998 Sep 15;161(6):3176-85
references.pmid: 9743386
references.citation: Semin Immunol. 1997 Oct;9(5):293-301
references.pmid: 9327524
references.citation: J Immunol Methods. 1999 Feb 1;223(1):77-92
references.pmid: 10037236
references.citation: Immunity. 2009 Feb 20;30(2):264-76
references.pmid: 19185517
references.citation: Immunol Cell Biol. 2008 Jan;86(1):31-9
references.pmid: 18026175
references.citation: Science. 2006 Jun 16;312(5780):1672-6
references.pmid: 16778060
references.citation: Eur J Immunol. 2008 Aug;38(8):2263-73
references.pmid: 18651710
references.citation: J Immunol. 2005 Dec 1;175(11):7125-34
references.pmid: 16301615
references.citation: J Immunol. 1999 Oct 15;163(8):4125-32
references.pmid: 10510347
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4782-7
references.pmid: 19255434
references.citation: J Immunol. 2002 Sep 15;169(6):2900-6
references.pmid: 12218103
references.citation: J Exp Med. 1997 Mar 3;185(5):941-51
references.pmid: 9120400
references.citation: Nature. 1987 May 7-13;327(6117):59-61
references.pmid: 3472080
references.citation: Mol Immunol. 1991 Mar;28(3):261-7
references.pmid: 1708106
references.citation: Nature. 2007 Nov 1;450(7166):110-4
references.pmid: 17934446
references.citation: Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):847-52
references.pmid: 10639168
references.citation: J Immunol. 1993 Oct 1;151(7):3557-68
references.pmid: 8376792
references.citation: J Immunol. 1998 Aug 1;161(3):1313-9
references.pmid: 9686593
references.citation: Nat Med. 2006 Feb;12(2):207-13
references.pmid: 16444266
references.citation: Scand J Immunol. 1998 Dec;48(6):563-70
references.pmid: 9874489
references.citation: Nature. 1998 Mar 19;392(6673):245-52
references.pmid: 9521319
references.citation: Biochem J. 1985 Oct 1;231(1):233-6
references.pmid: 4062888
references.citation: Science. 2007 Jan 5;315(5808):107-11
references.pmid: 17204652
references.citation: Immunity. 2007 Jul;27(1):160-71
references.pmid: 17658276
references.citation: Immunity. 2009 Mar 20;30(3):324-35
references.pmid: 19303387
references.citation: J Immunol. 2007 May 15;178(10):6200-7
references.pmid: 17475847
references.citation: Curr Opin Immunol. 2007 Jun;19(3):275-80
references.pmid: 17433651
references.citation: Eur J Immunol. 2006 Nov;36(11):2912-9
references.pmid: 17051619
references.citation: Hybrid Hybridomics. 2003 Feb;22(1):23-31
references.pmid: 12713687
references.citation: Immunity. 2007 Apr;26(4):491-502
references.pmid: 17379546
references.citation: Nat Immunol. 2007 Sep;8(9):992-1000
references.pmid: 17660822
references.citation: Immunity. 2005 Nov;23(5):503-14
references.pmid: 16286018
references.citation: Mol Immunol. 2005 May;42(8):979-85
references.pmid: 15829289
references.citation: Nat Rev Immunol. 2002 Mar;2(3):151-61
references.pmid: 11913066
references.citation: Immunol Rev. 2007 Aug;218:197-213
references.pmid: 17624954
references.citation: J Immunol. 2008 Jul 15;181(2):1375-85
references.pmid: 18606692
references.citation: Eur J Immunol. 1999 Nov;29(11):3712-21
references.pmid: 10556827
references.citation: Immunol Today. 2000 Sep;21(9):436-41
references.pmid: 10953095
references.citation: J Immunol. 1996 Aug 15;157(4):1406-14
references.pmid: 8759720
references.citation: J Biol Chem. 2000 Aug 4;275(31):23409-12
references.pmid: 10801898
references.citation: Int Immunopharmacol. 2001 Feb;1(2):265-75
references.pmid: 11360928
references.citation: J Immunol. 2009 Feb 15;182(4):2113-23
references.pmid: 19201864
references.citation: J Exp Med. 2008 Nov 24;205(12):2873-86
references.pmid: 18981236
references.citation: Eur J Immunol. 2005 Oct;35(10):2815-25
references.pmid: 16143986
references.citation: J Immunol. 1987 Feb 1;138(3):981-8
references.pmid: 2433338
references.citation: Blood. 2008 Oct 15;112(8):3264-73
references.pmid: 18669894
references.citation: Vaccine. 2005 Nov 16;23(46-47):5450-6
references.pmid: 16006019
references.citation: Mol Pharm. 2007 Jan-Feb;4(1):58-72
references.pmid: 17228857
references.citation: J Immunol. 2004 Aug 15;173(4):2297-306
references.pmid: 15294942
references.citation: J Exp Med. 1999 Sep 20;190(6):851-60
references.pmid: 10499923
references.citation: Proc Natl Acad Sci U S A. 1982 Jan;79(1):161-5
references.pmid: 6948298
references.citation: J Exp Med. 1990 May 1;171(5):1753-71
references.pmid: 2185332
references.citation: Eur J Immunol. 2004 Nov;34(11):2986-95
references.pmid: 15384042
references.citation: Semin Immunol. 1992 Aug;4(4):275-83
references.pmid: 1391800
references.citation: Nature. 2005 Nov 17;438(7066):364-8
references.pmid: 16292312
references.citation: Science. 2006 Dec 22;314(5807):1936-8
references.pmid: 17185603
references.citation: J Exp Med. 2000 Sep 18;192(6):813-21
references.pmid: 10993912