Comparable T helper 1 (Th1) and CD8 T-cell immunity by targeting HIV gag p24 to CD8 dendritic cells within antibodies to Langerin, DEC205, and Clec9A.
Improved protein-based vaccines should facilitate the goal of effective vaccines against HIV and other pathogens. With respect to T cells, the efficiency of immunization, or "immunogenicity," is improved by targeting vaccine proteins to maturing dendritic cells (DCs) within mAbs to DC receptors. Here, we compared the capacity of Langerin/CD207, DEC205/CD205, and Clec9A receptors, each expressed on the CD8(+) DC subset in mice, to bring about immunization of microbial-specific T cells from the polyclonal repertoire, using HIV gag-p24 protein as an antigen. α-Langerin mAb targeted splenic CD8(+) DCs selectively in vivo, whereas α-DEC205 and α-Clec9A mAbs targeted additional cell types. When the mAb heavy chains were engineered to express gag-p24, the α-Langerin, α-DEC205, and α-Clec9A fusion mAbs given along with a maturation stimulus induced comparable levels of gag-specific T helper 1 (Th1) and CD8(+) T cells in BALB/c × C57BL/6 F1 mice. These immune T cells were more numerous than targeting the CD8(-) DC subset with α-DCIR2-gag-p24. In an in vivo assay in which gag-primed T cells were used to report the early stages of T-cell responses, α-Langerin, α-DEC205, and α-Clec9A also mediated cross-presentation to primed CD8(+) T cells if, in parallel to antigen uptake, the DCs were stimulated with α-CD40. α-Langerin, α-DEC205, and α-Clec9A targeting greatly enhanced T-cell immunization relative to nonbinding control mAb or nontargeted HIV gag-p24 protein. Therefore, when the appropriate subset of DCs is targeted with a vaccine protein, several different receptors expressed by that subset are able to initiate combined Th1 and CD8(+) immunity.
Laboratory of Cellular Physiology and Immunology and The Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10065, USA.
Juliana
J
Idoyaga
Ashira
A
Lubkin
Christopher
C
Fiorese
Mireille H
MH
Lahoud
Irina
I
Caminschi
Yaoxing
Y
Huang
Anthony
A
Rodriguez
Björn E
BE
Clausen
Chae Gyu
CG
Park
Christine
C
Trumpfheller
Ralph M
RM
Steinman
D016915:AIDS Vaccines / Q000276:immunology* / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology*; D000954:Antigens, Surface / Q000276:immunology*; D016827:CD8 Antigens; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D016655:HIV Core Protein p24 / Q000276:immunology* / Q000494:pharmacology; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology*; D037241:Mannose-Binding Lectins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*
D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000954:Antigens, Surface; D016827:CD8 Antigens; C498497:Cd207 protein, mouse; C529914:Clec9a protein, mouse; C093569:DEC-205 receptor; D016655:HIV Core Protein p24; D037181:Lectins, C-Type; D037241:Mannose-Binding Lectins; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic
J Clin Invest. 2008 Jun;118(6):2098-110
18497879
Immunity. 2000 Jan;12(1):71-81
10661407
Science. 2007 Jan 5;315(5808):107-11
17204652
Cell Immunol. 1995 Jun;163(1):148-56
7758125
J Exp Med. 1986 Apr 1;163(4):981-97
3950549
J Exp Med. 2007 May 14;204(5):1095-106
17438065
J Exp Med. 2000 Dec 18;192(12):1685-96
11120766
J Exp Med. 2004 Mar 15;199(6):815-24
15024047
J Immunol. 2008 Mar 15;180(6):3647-50
18322168
Eur J Immunol. 2010 Jan;40(1):36-46
19830741
PLoS Pathog. 2009 Apr;5(4):e1000373
19360120
J Immunol. 1998 Sep 15;161(6):2985-93
9743362
J Immunol. 2001 Jul 15;167(2):741-8
11441078
J Exp Med. 2009 Mar 16;206(3):497-505
19221394
Nature. 2009 Jan 1;457(7225):87-91
18997770
J Biol Chem. 2008 Jun 13;283(24):16693-701
18408006
J Immunol Methods. 2007 Jul 31;324(1-2):48-62
17553520
Nat Rev Immunol. 2007 Jul;7(7):543-55
17589544
J Exp Med. 2002 Oct 21;196(8):1091-7
12391020
J Immunol. 2001 May 1;166(9):5327-30
11313367
Eur J Immunol. 1994 Aug;24(8):1828-34
7519997
J Exp Med. 2002 Sep 16;196(6):817-27
12235214
J Exp Med. 1997 Dec 1;186(11):1819-29
9382881
J Exp Med. 2006 Mar 20;203(3):607-17
16505141
Immunol Rev. 2010 Mar;234(1):18-31
20193009
J Immunol. 2001 May 1;166(9):5448-55
11313382
Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10729-34
16807294
Clin Vaccine Immunol. 2009 Dec;16(12):1709-19
19793898
J Immunol. 2006 Jul 1;177(1):372-82
16785533
Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1289-94
17229838
Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2574-9
18256187
Blood. 2008 Oct 15;112(8):3264-73
18669894
Eur J Immunol. 2010 Oct;40(10):2791-6
20812236
Nat Rev Immunol. 2007 Jan;7(1):19-30
17170756
Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1524-9
19168629
J Virol. 2004 Mar;78(6):2666-73
14990686
Proc Natl Acad Sci U S A. 1982 Jan;79(1):161-5
6948298
Nat Rev Immunol. 2002 Feb;2(2):77-84
11910898
Nature. 1995 May 11;375(6527):151-5
7753172
J Exp Med. 2009 Jul 6;206(7):1589-602
19564349
Immunology. 2008 Mar;123(3):339-47
18217955
Eur J Immunol. 2009 Apr;39(4):931-8
19197943
J Cell Biol. 2005 May 23;169(4):569-76
15897263
J Exp Med. 2001 Sep 17;194(6):769-79
11560993
J Exp Med. 2002 Dec 16;196(12):1627-38
12486105
J Exp Med. 2002 May 20;195(10):1289-302
12021309