Cross-competition of CD8+ T cells shapes the immunodominance hierarchy during boost vaccination.
CD8+ T cell responses directed against multiple pathogen-derived epitopes are characterized by defined immunodominance hierarchy patterns. A possible explanation for this phenomenon is that CD8+ T cells of different specificities compete for access to epitopes on antigen-presenting cells, and that the outcome of this so-called cross-competition reflects the number of induced T cells. In our study using a vaccinia virus infection model, we found that T cell cross-competition is highly relevant during boost vaccination, thereby shaping the immunodominance hierarchy in the recall. We demonstrate that competition was of no importance during priming and was unaffected by the applied route of immunization. It strongly depended on the timing of viral antigen expression in infected APCs, and it was characterized by poor proliferation of T cells recognizing epitopes derived from late viral proteins. To our knowledge, this is the first demonstration of the functional importance of T cell cross-competition during a viral infection. Our findings provide a basis for novel strategies for how boost vaccination to defined antigens can be selectively improved. They give important new insights into the design of more efficient poxviral vectors for immunotherapy.
Kastenmuller
Wolfgang
W
Institute of Molecular Virology, Antigen-specific Immunotherapy Clinical Cooperation Group, National Research Center for Environment and Health, 81675 Munich, Germany.
Gasteiger
Georg
G
Gronau
Julian H
JH
Baier
Robert
R
Ljapoci
Ronny
R
Busch
Dirk H
DH
Drexler
Ingo
I
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation; D002642:Chick Embryo; D045142:Cross-Priming / Q000276:immunology*; D005260:Female; D015967:Gene Expression Regulation, Viral; D005814:Genes, Viral / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D007117:Immunization, Secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D013997:Time Factors; D014611:Vaccination; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
D000956:Antigens, Viral; D014764:Viral Proteins
J Virol. 2000 Apr;74(8):3486-93
10729122
Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3183-8
9096367
Immunol Lett. 1999 Jan;65(1-2):93-8
10065633
J Exp Med. 1999 May 17;189(10):1591-600
10330438
Annu Rev Immunol. 1999;17:51-88
10358753
Cancer Res. 1999 Oct 1;59(19):4955-63
10519409
J Exp Med. 2005 Jan 3;201(1):95-104
15623576
J Exp Med. 2005 Apr 4;201(7):1031-6
15795239
Eur J Immunol. 1999 Oct;29(10):3112-21
10540322
J Virol. 2005 Oct;79(20):12703-13
16188973
J Immunol. 2000 Apr 15;164(8):4063-70
10754299
Biotechniques. 2000 Jun;28(6):1137-42, 1144-6, 1148
10868279
Nat Immunol. 2001 May;2(5):423-9
11323696
Nat Immunol. 2002 Jan;3(1):27-32
11731800
J Immunol. 2002 Jun 1;168(11):5387-91
12023329
J Virol. 2002 Oct;76(20):10332-7
12239309
Curr Opin Immunol. 2003 Feb;15(1):120-7
12495743
Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):217-22
12518065
Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13980-5
16172378
J Immunol. 2005 Oct 15;175(8):5504-15
16210659
Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):147-52
16373503
Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):994-9
16418289
Virology. 2006 Jul 5;350(2):276-88
16595141
Nat Biotechnol. 2006 Jul;24(7):817-9
16767078
Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):12063-8
16880405
J Immunol. 2006 Sep 1;177(5):2917-25
16920927
Immunity. 2006 Oct;25(4):533-43
17046682
Immunol Cell Biol. 2006 Dec;84(6):543-50
16956387
PLoS Comput Biol. 2006 Aug 18;2(8):e109
16933984
J Immunol. 2007 Mar 1;178(5):3091-8
17312156
Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6341-6
17400753
J Exp Med. 2007 Apr 16;204(4):941-9
17420267
J Exp Med. 2003 Apr 7;197(7):927-32
12668642
Immunity. 2003 Apr;18(4):499-511
12705853
Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7235-40
12775762
J Exp Med. 2003 Aug 4;198(3):399-410
12885871
J Immunol. 2003 Nov 15;171(10):5415-22
14607945
Methods Mol Biol. 2004;269:77-100
15114009
J Immunol. 2004 Jul 1;173(1):456-62
15210805
J Immunol. 2004 Oct 15;173(8):5021-7
15470045
Cell Immunol. 1995 Oct 1;165(1):55-64
7545549
J Exp Med. 1997 Jun 16;185(12):2043-51
9182675