Abstract
Human immunodeficiency virus type-1 (HIV-1)-specific dendritic cell (DC) vaccines have been used in clinical trials. However, they have been found to only induce some degree of immune responses in these studies. We previously demonstrated that the HIV-1 Gag-specific Gag-Texo vaccine stimulated Gag-specific effector CD8+ cytotoxic T lymphocyte (CTL) responses, leading to completely protective, but very limited, therapeutic immunity. In this study, we constructed a recombinant adenoviral vector, adenovirus (AdV)4-1BBL, which expressed mouse 4-1BB ligand (4-1BBL), and generated transgenic 4-1BBL-engineered OVA-Texo/4-1BBL and Gag-Texo/4-1BBL vaccines by transfecting ovalbumin (OVA)-Texo and Gag-Texo cells with AdV4-1BBL, respectively. We demonstrate that the OVA-specific OVA-Texo/4-1BBL vaccine stimulates more efficient OVA-specific CTL responses (3.26%) compared to OVA-Texo-activated responses (1.98%) in wild-type C57BL/6 mice and the control OVA-Texo/Null vaccine without transgenic 4-1BBL expression, leading to enhanced therapeutic immunity against 6-day established OVA-expressing B16 melanoma BL6-10OVA cells. OVA-Texo/4-1BBL-stimulated CTLs, which have a CD44+CD62Lhigh IL-7R+ phenotype, are likely memory CTL precursors, demonstrating prolonged survival and enhanced differentiation into memory CTLs with functional recall responses and long-term immunity against BL6-10OVA melanoma. In addition, we demonstrate that OVA-Texo/4-1BBL-stimulated CTLs up- and downregulate the expression of anti-apoptosis (Bcl2l10, Naip1, Nol3, Pak7 and Tnfrsf11b) and pro-apoptosis (Casp12, Trp63 and Trp73) genes, respectively, by RT2 Profiler PCR array analysis. Importantly, the Gag-specific Gag-Texo/4-1BBL vaccine also stimulates more efficient Gag-specific therapeutic and long-term immunity against HLA-A2/Gag-expressing B16 melanoma BL6-10Gag/A2 cells than the control Gag-Texo/Null vaccine in transgenic HLA-A2 mice. Taken together, our novel Gag-Texo/4-1BBL vaccine, which is capable of stimulating potent Gag-specific therapeutic and long-term immunity, may represent a new immunotherapeutic vaccine for controlling HIV-1 infection.
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References
McMichael A, Hanke T . The quest for an AIDS vaccine: is the CD8+ T-cell approach feasible? Nat Rev Immunol 2002; 2: 283–291.
Mudd PA, Martins MA, Ericsen AJ, Tully DC, Power KA, Bean AT et al. Vaccine-induced CD8+ T cells control AIDS virus replication. Nature 2012; 491: 129–133.
Lapenta C, Santini SM, Logozzi M, Spada M, Andreotti M, Di Pucchio T et al. Potent immune response against HIV-1 and protection from virus challenge in hu-PBL-SCID mice immunized with inactivated virus-pulsed dendritic cells generated in the presence of IFN-alpha. J Exp Med 2003; 198: 361–367.
Yoshida A, Tanaka R, Murakami T, Takahashi Y, Koyanagi Y, Nakamura M et al. Induction of protective immune responses against R5 human immunodeficiency virus type 1 (HIV-1) infection in hu-PBL-SCID mice by intrasplenic immunization with HIV-1-pulsed dendritic cells: possible involvement of a novel factor of human CD4+ T-cell origin. J Virol 2003; 77: 8719–8728.
Villamide-Herrera L, Ignatius R, Eller MA, Wilkinson K, Griffin C, Mehlhop E et al. Macaque dendritic cells infected with SIV-recombinant canarypox ex vivo induce SIV-specific immune responses in vivo. AIDS Res Hum Retroviruses 2004; 20: 871–884.
Carbonneil C, Aouba A, Burgard M, Cardinaud S, Rouzioux C, Langlade-Demoyen P et al. Dendritic cells generated in the presence of granulocyte-macrophage colony-stimulating factor and IFN-alpha are potent inducers of HIV-specific CD8 T cells. AIDS 2003; 17: 1731–1740.
Garcia F, Routy JP . Challenges in dendritic cells-based therapeutic vaccination in HIV-1 infection Workshop in dendritic cell-based vaccine clinical trials in HIV-1. Vaccine 2011; 29: 6454–6463.
Hao S, Liu Y, Yuan J, Zhang X, He T, Wu X et al. Novel exosome-targeted CD4+ T cell vaccine counteracting CD4+25+ regulatory T cell-mediated immune suppression and stimulating efficient central memory CD8+ CTL responses. J Immunol 2007; 179: 2731–2740.
Hao S, Yuan J, Xiang J . Nonspecific CD4+ T cells with uptake of antigen-specific dendritic cell-released exosomes stimulate antigen-specific CD8+ CTL responses and long-term T cell memory. J Leuk Biol 2007; 82: 829–838.
Xie Y, Wang L, Freywald A, Qureshi M, Chen Y, Xiang J . A novel T cell-based vaccine capable of stimulating long-term functional CTL memory against B16 melanoma via CD40L signaling. Cell Mol Immunol 2013; 10: 72–77.
Nanjundappa RH, Wang R, Xie Y, Umeshappa CS, Chibbar R, Wei Y et al. GP120-specific exosome-targeted T cell-based vaccine capable of stimulating DC- and CD4+ T-independent CTL responses. Vaccine 2011; 29: 3538–3547.
Nanjundappa RH, Wang R, Xie Y, Umeshappa CS, Xiang J . Novel CD8+ T cell-based vaccine stimulates Gp120-specific CTL responses leading to therapeutic and long-term immunity in transgenic HLA-A2 mice. Vaccine 2012; 30: 3519–3525.
Wang R, Xie Y, Zhao T, Tan X, Xu J, Xiang J . HIV-1 Gag-specific exosome-targeted T cell-based vaccine stimulates effector CTL responses leading to therapeutic and long-term immunity against Gag/HLA-A2-expressing B16 melanoma in transgenic HLA-A2 mice. Trials Vaccinol 2014; 3: 19–25.
Wang C, Lin GH, McPherson AJ, Watts TH . Immune regulation by 4-1BB and 4-1BBL: complexities and challenges. Immunol Rev 2009; 229: 192–215.
Takahashi C, Mittler RS, Vella AT . Cutting edge: 4-1BB is a bona fide CD8 T cell survival signal. J Immunol 1999; 162: 5037–5040.
Bertram EM, Lau P, Watts TH . Temporal segregation of 4-1BB versus CD28-mediated costimulation: 4-1BB ligand influences T cell numbers late in the primary response and regulates the size of the T cell memory response following influenza infection. J Immunol 2002; 168: 3777–3785.
Lee HW, Park SJ, Choi BK, Kim HH, Nam KO, Kwon BS . 4-1BB promotes the survival of CD8+ T lymphocytes by increasing expression of Bcl-xL and Bfl-1. J Immunol 2002; 169: 4882–4888.
Pulle G, Vidric M, Watts TH . IL-15-dependent induction of 4-1BB promotes antigen-independent CD8 memory T cell survival. J Immunol 2006; 176: 2739–2748.
Moraes TJ, Lin GH, Wen T, Watts TH . Incorporation of 4-1BB ligand into an adenovirus vaccine vector increases the number of functional antigen-specific CD8 T cells and enhances the duration of protection against influenza-induced respiratory disease. Vaccine 2011; 29: 6301–6312.
Habib-Agahi M, Phan TT, Searle PF . Co-stimulation with 4-1BB ligand allows extended T-cell proliferation, synergizes with CD80/CD86 and can reactivate anergic T cells. Int Immunol 2007; 19: 1383–1394.
Vezys V, Penaloza-MacMaster P, Barber DL, Ha SJ, Konieczny B, Freeman GJ et al. 4-1BB signaling synergizes with programmed death ligand 1 blockade to augment CD8 T cell responses during chronic viral infection. J Immunol 2011; 187: 1634–1642.
Wang C, Wen T, Routy JP, Bernard NF, Sekaly RP, Watts TH . 4-1BBL induces TNF receptor-associated factor 1-dependent Bim modulation in human T cells and is a critical component in the costimulation-dependent rescue of functionally impaired HIV-specific CD8 T cells. J Immunol 2007; 179: 8252–8263.
De Keersmaecker B, Heirman C, Corthals J, Empsen C, van Grunsven LA, Allard SD et al. The combination of 4-1BBL and CD40L strongly enhances the capacity of dendritic cells to stimulate HIV-specific T cell responses. J Leuk Biol 2011; 89: 989–999.
Shi M, Hao S, Chan T, Xiang J . CD4+ T cells stimulate memory CD8+ T cell expansion via acquired pMHC I complexes and costimulatory molecules, and IL-2 secretion. J Leuk Biol 2006; 80: 1354–1363.
Umeshappa CS, Xie Y, Xu S, Nanjundappa RH, Freywald A, Deng Y et al. Th cells promote CTL survival and memory via acquired pMHC-I and endogenous IL-2 and CD40L signaling and by modulating apoptosis-controlling pathways. PloS One 2013; 8: e64787.
Lefrancois L, Obar JJ . Once a killer, always a killer: from cytotoxic T cell to memory cell. Immunol Rev 2010; 235: 206–218.
Rathmell JC, Thompson CB . The central effectors of cell death in the immune system. Annu Rev Immunol 1999; 17: 781–828.
Olson SY, Garban HJ . Regulation of apoptosis-related genes by nitric oxide in cancer. Nitric Oxide 2008; 19: 170–176.
Starck L, Scholz C, Dorken B, Daniel PT . Costimulation by CD137/4-1BB inhibits T cell apoptosis and induces Bcl-xL and c-FLIP(short) via phosphatidylinositol 3-kinase and AKT/protein kinase B. Eur J Immunol 2005; 35: 1257–1266.
Sabbagh L, Andreeva D, Laramee GD, Oussa NA, Lew D, Bisson N et al. Leukocyte-specific protein 1 links TNF receptor-associated factor 1 to survival signaling downstream of 4-1BB in T cells. J Leuk Biol 2013; 93: 713–721.
Kang YJ, Kim SO, Shimada S, Otsuka M, Seit-Nebi A, Kwon BS et al. Cell surface 4-1BBL mediates sequential signaling pathways ‘downstream' of TLR and is required for sustained TNF production in macrophages. Nat Immunol 2007; 8: 601–609.
Gelman AE, Zhang J, Choi Y, Turka LA . Toll-like receptor ligands directly promote activated CD4+ T cell survival. J Immunol 2004; 172: 6065–6073.
Cottalorda A, Verschelde C, Marcais A, Tomkowiak M, Musette P, Uematsu S et al. TLR2 engagement on CD8 T cells lowers the threshold for optimal antigen-induced T cell activation. Eur J Immunol 2006; 36: 1684–1693.
Quigley M, Martinez J, Huang X, Yang Y . A critical role for direct TLR2–MyD88 signaling in CD8 T-cell clonal expansion and memory formation following vaccinia viral infection. Blood 2009; 113: 2256–2264.
Calzascia T, Pellegrini M, Hall H, Sabbagh L, Ono N, Elford AR et al. TNF-alpha is critical for antitumor but not antiviral T cell immunity in mice. J Clin Invest 2007; 117: 3833–3845.
Kim EY, Priatel JJ, Teh SJ, Teh HS . TNF receptor type 2 (p75) functions as a costimulator for antigen-driven T cell responses in vivo. J Immunol 2006; 176: 1026–1035.
Parker SD, Rottinghaus ST, Zajac AJ, Yue L, Hunter E, Whitley RJ et al. HIV-1(89.6) Gag expressed from a replication competent HSV-1 vector elicits persistent cellular immune responses in mice. Vaccine 2007; 25: 6764–6773.
Li W, Li S, Hu Y, Tang B, Cui L, He W . Efficient augmentation of a long-lasting immune responses in HIV-1 gag DNA vaccination by IL-15 plasmid boosting. Vaccine 2008; 26: 3282–3290.
Niu L, Termini JM, Kanagavelu SK, Gupta S, Rolland MM, Kulkarni V et al. Preclinical evaluation of HIV-1 therapeutic ex vivo dendritic cell vaccines expressing consensus Gag antigens and conserved Gag epitopes. Vaccine 2011; 29: 2110–2119.
Liu Y, Li F, Liu Y, Hong K, Meng X, Chen J et al. HIV fragment gag vaccine induces broader T cell response in mice. Vaccine 2011; 29: 2582–2589.
Miura T, Brockman MA, Schneidewind A, Lobritz M, Pereyra F, Rathod A et al. HLA-B57/B*5801 human immunodeficiency virus type 1 elite controllers select for rare gag variants associated with reduced viral replication capacity and strong cytotoxic T-lymphocyte [corrected] recognition. J Virol 2009; 83: 2743–2755.
Zuniga R, Lucchetti A, Galvan P, Sanchez S, Sanchez C, Hernandez A et al. Relative dominance of Gag p24-specific cytotoxic T lymphocytes is associated with human immunodeficiency virus control. J Virol 2006; 80: 3122–3125.
Kiepiela P, Ngumbela K, Thobakgale C, Ramduth D, Honeyborne I, Moodley E et al. CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat Med 2007; 13: 46–53.
Rolland M, Heckerman D, Deng W, Rousseau CM, Coovadia H, Bishop K et al. Broad and Gag-biased HIV-1 epitope repertoires are associated with lower viral loads. PloS One 2008; 3: e1424.
Julg B, Williams KL, Reddy S, Bishop K, Qi Y, Carrington M et al. Enhanced anti-HIV functional activity associated with Gag-specific CD8 T-cell responses. J Virol 2010; 84: 5540–5549.
Huang Y, Qiu C, Liu LX, Feng YM, Zhu T, Xu JQ . A mouse model based on replication-competent Tiantan vaccinia expressing luciferase/HIV-1 Gag fusion protein for the evaluation of protective efficacy of HIV vaccine. Chin Med J 2009; 122: 1655–1659.
Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 1996; 8: 765–772.
Zinselmeyer BH, Heydari S, Sacristan C, Nayak D, Cammer M, Herz J et al. PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis. J Exp Med 2013; 210: 757–774.
Chikuma S, Terawaki S, Hayashi T, Nabeshima R, Yoshida T, Shibayama S et al. PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo. J Immunol 2009; 182: 6682–6689.
Dai H, Wan N, Zhang S, Moore Y, Wan F, Dai Z . Cutting edge: programmed death-1 defines CD8+CD122+ T cells as regulatory versus memory T cells. J Immunol 2010; 185: 803–807.
Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006; 439: 682–687.
Gavioli R, Cellini S, Castaldello A, Voltan R, Gallerani E, Gagliardoni F et al. The Tat protein broadens T cell responses directed to the HIV-1 antigens Gag and Env: implications for the design of new vaccination strategies against AIDS. Vaccine 2008; 26: 727–737.
Ferrantelli F, Maggiorella MT, Schiavoni I, Sernicola L, Olivieri E, Farcomeni S et al. A combination HIV vaccine based on Tat and Env proteins was immunogenic and protected macaques from mucosal SHIV challenge in a pilot study. Vaccine 2011; 29: 2918–2932.
Acknowledgements
This research was supported by research grants (OCH 126276) from the Canadian Institutes of Health Research and the Beijing Science and Technology Foundation (5121002).
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Wang, R., Freywald, A., Chen, Y. et al. Transgenic 4-1BBL-engineered vaccine stimulates potent Gag-specific therapeutic and long-term immunity via increased priming of CD44+CD62Lhigh IL-7R+ CTLs with up- and downregulation of anti- and pro-apoptosis genes. Cell Mol Immunol 12, 456–465 (2015). https://doi.org/10.1038/cmi.2014.72
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DOI: https://doi.org/10.1038/cmi.2014.72
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