title: Novel exosome-targeted CD4+ T cell vaccine counteracting CD4+25+ regulatory T cell-mediated immune suppression and stimulating efficient central memory CD8+ CTL responses.
abstract: T cell-to-T cell Ag presentation is increasingly attracting attention. In this study, we demonstrated that active CD4+ T (aT) cells with uptake of OVA-pulsed dendritic cell-derived exosome (EXO(OVA)) express exosomal peptide/MHC class I and costimulatory molecules. These EXO(OVA)-uptaken (targeted) CD4+ aT cells can stimulate CD8+ T cell proliferation and differentiation into central memory CD8+ CTLs and induce more efficient in vivo antitumor immunity and long-term CD8+ T cell memory responses than OVA-pulsed dendritic cells. They can also counteract CD4+25+ regulatory T cell-mediated suppression of in vitro CD8+ T cell proliferation and in vivo CD8+ CTL responses and antitumor immunity. We further elucidate that the EXO(OVA)-uptaken (targeted)CD4+ aT cell's stimulatory effect is mediated via its IL-2 secretion and acquired exosomal CD80 costimulation and is specifically delivered to CD8+ T cells in vivo via acquired exosomal peptide/MHC class I complexes. Therefore, EXO-targeted active CD4+ T cell vaccine may represent a novel and highly effective vaccine strategy for inducing immune responses against not only tumors, but also other infectious diseases.
authors: Department of Oncology and Immunology, Division of Health Research, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors: Siguo
authors: S
authors: Hao
authors: Yongqing
authors: Y
authors: Liu
authors: Jinying
authors: J
authors: Yuan
authors: Xueshu
authors: X
authors: Zhang
authors: Tianpei
authors: T
authors: He
authors: Xiaochu
authors: X
authors: Wu
authors: Yangdou
authors: Y
authors: Wei
authors: Deming
authors: D
authors: Sun
authors: Jim
authors: J
authors: Xiang
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007156:Immunologic Memory; D007165:Immunosuppression Therapy; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008213:Lymphocyte Activation; D051379:Mice; D009369:Neoplasms / Q000276:immunology*; D010047:Ovalbumin / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D018122:B7-1 Antigen; D015704:CD4 Antigens; D016827:CD8 Antigens; D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D053645:Interleukin-2 Receptor alpha Subunit; D010047:Ovalbumin
references: J Exp Med. 2001 Jun 4;193(11):1295-302
references: 11390436
references: J Immunol. 2001 May 15;166(10):6099-103
references: 11342628
references: Int Immunol. 2002 Jul;14(7):713-22
references: 12096030
references: J Immunol. 2002 Sep 1;169(5):2756-61
references: 12193750
references: Nat Immunol. 2002 Dec;3(12):1156-62
references: 12426563
references: Nat Rev Immunol. 2002 Dec;2(12):982-7
references: 12461571
references: Immunology. 2003 Feb;108(2):177-88
references: 12562326
references: J Immunol. 2003 Feb 15;170(4):1675-82
references: 12574330
references: Science. 2003 Feb 14;299(5609):1033-6
references: 12532024
references: Eur J Immunol. 2003 Feb;33(2):502-11
references: 12645949
references: Nat Rev Immunol. 2003 Mar;3(3):253-7
references: 12658273
references: Blood. 2003 Jun 1;101(11):4260-6
references: 12576317
references: Nature. 2003 Sep 25;425(6956):397-402
references: 14508489
references: J Immunol. 2003 Dec 1;171(11):5678-82
references: 14634074
references: Nat Immunol. 2003 Dec;4(12):1191-8
references: 14625547
references: J Immunol. 2004 Feb 15;172(4):2126-36
references: 14764678
references: J Immunol. 2004 Feb 15;172(4):2137-46
references: 14764679
references: J Immunol. 2004 Mar 15;172(6):3391-8
references: 15004137
references: J Immunol. 2004 Apr 15;172(8):4676-80
references: 15067041
references: Nat Med. 2004 Sep;10(9):942-9
references: 15322536
references: Int Immunol. 2004 Oct;16(10):1523-33
references: 15351785
references: J Clin Invest. 1993 Feb;91(2):388-90
references: 8432846
references: Semin Surg Oncol. 1996 Nov-Dec;12(6):446-53
references: 8914209
references: Nature. 1998 Mar 19;392(6673):245-52
references: 9521319
references: Nat Med. 1998 May;4(5 Suppl):525-31
references: 9585204
references: Nat Med. 1998 May;4(5):594-600
references: 9585234
references: Annu Rev Immunol. 1998;16:201-23
references: 9597129
references: J Exp Med. 1998 Jul 20;188(2):287-96
references: 9670041
references: Int Immunol. 1998 Dec;10(12):1969-80
references: 9885918
references: Int J Cancer. 2005 Apr 20;114(4):613-22
references: 15609328
references: J Immunol. 2005 Apr 1;174(7):3967-77
references: 15778353
references: J Immunol. 2005 May 1;174(9):5341-50
references: 15843531
references: J Immunol. 2005 Jun 15;174(12):7497-505
references: 15944248
references: Blood. 2005 Aug 1;106(3):1008-11
references: 15840697
references: J Immunol. 2005 Aug 1;175(3):1433-9
references: 16034079
references: J Immunol. 2005 Sep 1;175(5):2931-7
references: 16116179
references: J Immunol. 2005 Dec 1;175(11):7274-80
references: 16301632
references: Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5024-9
references: 16547138
references: Immunology. 2007 Jan;120(1):90-102
references: 17073943
references: Int Immunol. 2006 Jun;18(6):887-95
references: 16621867
references: J Exp Med. 2000 Apr 3;191(7):1137-48
references: 10748232
references: J Cell Sci. 2000 Oct;113 Pt 19:3365-74
references: 10984428
references: J Mol Cell Cardiol. 2000 Dec;32(12):2269-77
references: 11113002
references: J Immunol Methods. 2001 Jan 1;247(1-2):163-74
references: 11150547
references: Traffic. 2001 Feb;2(2):124-37
references: 11247303
references: Nat Immunol. 2000 Oct;1(4):285-9
references: 11017098
references: J Immunol. 2001 Apr 15;166(8):5099-107
references: 11290791
references: J Exp Med. 2002 Jun 17;195(12):1523-32
references: 12070280