We hypothesize that over-expression of transporters associated with antigen processing (TAP1 and TAP2), components of the major histocompatibility complex (MHC) class I antigen-processing pathway, enhances antigen-specific cytotoxic activity in response to viral infection. An expression system using recombinant vaccinia virus (VV) was used to over-express human TAP1 and TAP2 (VV-hTAP1,2) in normal mice. Mice coinfected with either vesicular stomatitis virus plus VV-hTAP1,2 or Sendai virus plus VV-hTAP1,2 increased cytotoxic lymphocyte (CTL) activity by at least 4-fold when compared to coinfections with a control vector, VV encoding the plasmid PJS-5. Coinfections with VV-hTAP1,2 increased virus-specific CTL precursors compared to control infections without VV-hTAP1,2. In an animal model of lethal viral challenge after vaccination, VV-hTAP1,2 provided protection against a lethal challenge of VV at doses 100-fold lower than control vector alone. Mechanistically, the total MHC class I antigen surface expression and the cross-presentation mechanism in spleen-derived dendritic cells was augmented by over-expression of TAP. Furthermore, VV-hTAP1,2 increases splenic TAP transport activity and endogenous antigen processing, thus rendering infected targets more susceptible to CTL recognition and subsequent killing. This is the first demonstration that over-expression of a component of the antigen-processing machinery increases endogenous antigen presentation and dendritic cell cross-presentation of exogenous antigens and may provide a novel and general approach for increasing immune responses against pathogens at low doses of vaccine inocula.
References
[1]
Zinkernagel RM, Doherty PC (1979) MHC-restricted cytotoxic T cells: Studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness. Adv Immunol 27: 51–177.
[2]
Townsend AR, Rothbard J, Gotch FM, Bahadur G, Wraith D, et al. (1986) The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell 44: 959–968.
[3]
Suh WK, Cohen-Doyle MF, Fruh K, Wang K, Peterson PA, et al. (1994) Interaction of MHC class I molecules with the transporter associated with antigen processing. Science 264: 1322–1326.
[4]
Frisan T, Zhang QJ, Levitskaya J, Coram M, Kurilla MG, et al. (1996) Defective presentation of MHC class I-restricted cytotoxic T-cell epitopes in Burkitt's lymphoma cells. Int J Cancer 68: 251–258.
[5]
Alimonti J, Zhang QJ, Gabathuler R, Reid G, Chen SS, et al. (2000) TAP expression provides a general method for improving the recognition of malignant cells in vivo. Nat Biotechnol 18: 515–520.
[6]
Deverson EV, Gow IR, Coadwell WJ, Monaco JJ, Butcher GW, et al. (1990) MHC class II region encoding proteins related to the multidrug resistance family of transmembrane transporters. Nature 348: 738–741.
[7]
Kelly A, Powis SH, Glynne R, Radley E, Beck S, et al. (1991) Second proteasome-related gene in the human MHC class II region. Nature 353: 667–668.
[8]
Norbury CC, Princiotta MF, Bacik I, Brutkiewicz RR, Wood P, et al. (2001) Multiple antigen-specific processing pathways for activating naive CD8+ T cells in vivo. J Immunol 166: 4355–4362.
[9]
Ortmann B, Androlewicz MJ, Cresswell P (1994) MHC class I/beta 2-microglobulin complexes associate with TAP transporters before peptide binding. Nature 368: 864–867.
[10]
Belyakov IM, Earl P, Dzutsev A, Kuznetsov VA, Lemon M, et al. (2003) Shared modes of protection against poxvirus infection by attenuated and conventional smallpox vaccine viruses. Proc Natl Acad Sci U S A 100: 9458–9463.
[11]
Takahashi H, Takeshita T, Morein B, Putney S, Germain RN, et al. (1990) Induction of CD8+ cytotoxic T cells by immunization with purified HIV-1 envelope protein in ISCOMs. Nature 344: 873–875.
[12]
Salter RD, Cresswell P (1986) Impaired assembly and transport of HLA-A and -B antigens in a mutant TxB cell hybrid. EMBO J 5: 943–949.
[13]
Spies T, DeMars R (1991) Restored expression of major histocompatibility class I molecules by gene transfer of a putative peptide transporter. Nature 351: 323–324.
[14]
Smith GL, Symons JA, Khanna A, Vanderplasschen A, Alcami A (1997) Vaccinia virus immune evasion. Immunol Rev 159: 137–154.
[15]
Hooper JW, Custer DM, Schmaljohn CS, Schmaljohn AL (2000) DNA vaccination with vaccinia virus L1R and A33R genes protects mice against a lethal poxvirus challenge. Virology 266: 329–339.
[16]
Brandt TA, Jacobs BL (2001) Both carboxy- and amino-terminal domains of the vaccinia virus interferon resistance gene, E3L, are required for pathogenesis in a mouse model. J Virol 75: 850–856.
[17]
Smee DF, Bailey KW, Sidwell RW (2001) Treatment of lethal vaccinia virus respiratory infections in mice with cidofovir. Antivir Chem Chemother 12: 71–76.
[18]
Reading PC, Smith GL (2003) Vaccinia virus interleukin-18-binding protein promotes virulence by reducing gamma interferon production and natural killer and T-cell activity. J Virol 77: 9960–9968.
[19]
Bellone M, Iezzi G, Manfredi AA, Protti MP, Dellabona P, et al. (1994) In vitro priming of cytotoxic T lymphocytes against poorly immunogenic epitopes by engineered antigen-presenting cells. Eur J Immunol 24: 2691–2698.
[20]
Momburg F, Neefjes JJ, Hammerling GJ (1994) Peptide selection by MHC-encoded TAP transporters. Curr Opin Immunol 6: 32–37.
[21]
Uebel S, Meyer TH, Kraas W, Kienle S, Jung G, et al. (1995) Requirements for peptide binding to the human transporter associated with antigen processing revealed by peptide scans and complex peptide libraries. J Biol Chem 270: 18512–18516.
[22]
Motta I, Lone YC, Kourilsky P (1998) In vitro induction of naive cytotoxic T lymphocytes with complexes of peptide and recombinant MHC class I molecules coated onto beads: Role of TCR/ligand density. Eur J Immunol 28: 3685–3695.
[23]
Armandola EA, Momburg F, Nijenhuis M, Bulbuc N, Fruh K, et al. (1996) A point mutation in the human transporter associated with antigen processing (TAP2) alters the peptide transport specificity. Eur J Immunol 26: 1748–1755.
[24]
van Endert PM, Riganelli D, Greco G, Fleischhauer K, Sidney J, et al. (1995) The peptide-binding motif for the human transporter associated with antigen processing. J Exp Med 182: 1883–1895.
[25]
Momburg F, Roelse J, Howard JC, Butcher GW, Hammerling GJ, et al. (1994) Selectivity of MHC-encoded peptide transporters from human, mouse and rat. Nature 367: 648–651.
[26]
Lizee G, Basha G, Tiong J, Julien JP, Tian M, et al. (2003) Control of dendritic cell cross-presentation by the major histocompatibility complex class I cytoplasmic domain. Nat Immunol 4: 1065–1073.
[27]
Guermonprez P, Saveanu L, Kleijmeer M, Davoust J, Van Endert P, et al. (2003) ER-phagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells. Nature 425: 397–402.
[28]
Chen L, Jondal M (2004) Endolysosomal processing of exogenous antigen into major histocompatibility complex class I-binding peptides. Scand J Immunol 59: 545–552.
[29]
Chen L, Jondal M (2004) Alternative processing for MHC class I presentation by immature and CpG-activated dendritic cells. Eur J Immunol 34: 952–960.
[30]
Seliger B, Wollscheid U, Momburg F, Blankenstein T, Huber C (2001) Characterization of the major histocompatibility complex class I deficiencies in B16 melanoma cells. Cancer Res 61: 1095–1099.
[31]
Reits EA, Vos JC, Gromme M, Neefjes J (2000) The major substrates for TAP in vivo are derived from newly synthesized proteins. Nature 404: 774–778.
[32]
Bacik I, Cox JH, Anderson R, Yewdell JW, Bennink JR (1994) TAP (transporter associated with antigen processing)-independent presentation of endogenously synthesized peptides is enhanced by endoplasmic reticulum insertion sequences located at the amino- but not carboxyl-terminus of the peptide. J Immunol 152: 381–387.
[33]
Ackerman AL, Kyritsis C, Tampe R, Cresswell P (2003) Early phagosomes in dendritic cells form a cellular compartment sufficient for cross presentation of exogenous antigens. Proc Natl Acad Sci U S A 100: 12889–12894.
[34]
Houde M, Bertholet S, Gagnon E, Brunet S, Goyette G, et al. (2003) Phagosomes are competent organelles for antigen cross-presentation. Nature 425: 402–406.
Singh M, O'Hagan D (1999) Advances in vaccine adjuvants. Nat Biotechnol 17: 1075–1081.
[38]
Kahn P (2002) NIH drops plans for phase III trials. IAVI Rep 6(1): 1–16.
[39]
Russ G, Esquivel F, Yewdell JW, Cresswell P, Spies T, et al. (1995) Assembly, intracellular localization, and nucleotide binding properties of the human peptide transporters TAP1 and TAP2 expressed by recombinant vaccinia viruses. J Biol Chem 270: 21312–21318.
[40]
Norbury CC, Princiotta MF, Bacik I, Brutkiewicz RR, Wood P, et al. (2001) Multiple antigen-specific processing pathways for activating naive CD8+ T cells in vivo. J Immunol 166: 4355–4362.
[41]
Androlewicz MJ, Anderson KS, Cresswell P (1993) Evidence that transporters associated with antigen processing translocate a major histocompatibility complex class I-binding peptide into the endoplasmic reticulum in an ATP-dependent manner. Proc Natl Acad Sci U S A 90: 9130–9134.
[42]
Heemels MT, Schumacher TN, Wonigeit K, Ploegh HL (1993) Peptide translocation by variants of the transporter associated with antigen processing. Science 262: 2059–2063.
[43]
Porgador A, Yewdell JW, Deng Y, Bennink JR, Germain RN (1997) Localization, quantitation, and in situ detection of specific peptide-MHC class I complexes using a monoclonal antibody. Immunity 6: 715–726.
