The current DNA vaccine formulations are not optimal for stimulation of CD8+ T cells, which are required for clearing virally-infected cells. Here we show that CD8+ T cell-stimulating activity can be effectively augmented by combining DNA vaccination with protein transfer. C57BL/6 mice were injected intramuscularly with an anti-SARS-CoV DNA vaccine admixed with a lipid-derived conjugate of 4-1BBL, a potential CD8+ T-cell co-stimulator. The inclusion of the lipidated co-stimulator greatly enhanced cellular immune responses, especially the CTL response, induced by the DNA vaccine. The adjuvant effect of 4-1BBL was lipidation-dependent, indicating that it functions as a cell membrane–anchored co-stimulator. Results of our study suggest, for the first time, that muscle cells may be modified in situ, at the DNA injection site, into APC-like cells to allow direct priming of CD8+ T cells and thereby improve the efficacy of DNA vaccines.
Get full access to this article
View all access options for this article.
References
1.
ChenA, ZhengG, TykocinskiML. Hierarchical costimulator thresholds for distinct immune responses: Application of a novel two-step Fc fusion protein transfer method. J Immunol, 2000; 164:705–711.
2.
ChenZ, PeiD, JiangLet al.Antigenicity analysis of different regions of the severe acute respiratory syndrome coronavirus nucleocapsid protein. Clin Chem, 2004; 50:988–995.
3.
CroftM. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity?Nat Rev Immunol, 2003; 3:609–620.
4.
GoebelsN, MichaelisD, WekerleH, HohlfeldR. Human myoblasts as antigen-presenting cells. J Immunol, 1992; 149:661–667.
5.
HohlfeldR, EngelAG. The immunobiology of muscle. Immunol Today, 1994; 15:269–274.
6.
HuangJ, CaoY, DuJ, BuX, MaR, WuC. Priming with SARS CoV S DNA and boosting with SARS CoV S epitopes specific for CD4+ and CD8+ T cells promote cellular immune responses. Vaccine, 2007; 25:6981–6991.
7.
HuangJ, MaR, WuCY. Immunization with SARS-CoV S DNA vaccine generates memory CD4+ and CD8+ T cell immune responses. Vaccine, 2006; 24:4905–4913.
8.
HuangJH, GettyRR, ChisariFV, FowlerP, GreenspanNS, TykocinskiML. Protein transfer of preformed MHC-peptide complexes sensitizes target cells to T cell cytolysis. Immunity, 1994; 1:607–613.
9.
JinH, XiaoC, ChenZet al.Induction of Th1 type response by DNA vaccinations with N, M, and E genes against SARS-CoV in mice. Biochem Biophys Res Commun, 2005; 328:979–986.
10.
JuneCH, BluestoneJA, NadlerLM, ThompsonCB. The B7 and CD28 receptor families. Immunol Today, 1994; 15:321–331.
11.
KsiazekTG, ErdmanD, GoldsmithCSSet al.A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med, 2003; 348:1953–1966.
12.
KwonB, LeeHW, KwonBS. New insights into the role of 4-1BB in immune responses: beyond CD8+ T cells. Trends Immunol, 2002; 23:378–380.
13.
LaiMM. SARS virus: the beginning of the unraveling of a new coronavirus. J Biomed Sci, 2003; 10:664–675.
14.
LiuS, FosterBA, ChenT, ZhengG, ChenA. Modifying dendritic cells via protein transfer for antitumor therapeutics. Clin Cancer Res, 2007; 13:283–291.
15.
MarraMA, JonesSJM, AstellCRet al.The genome sequence of the SARS-associated coronavirus. Science, 2003; 300:1399–1404.
16.
McShaneH, BrookesR, GilbertSC, HillAVS. Enhanced immunogenicity of CD4+ T-cell responses and protective efficacy of a DNA-modified vaccinia virus Ankara prime-boost vaccination regimen for murine tuberculosis. Infect Immun, 2001; 69:681–686.
17.
O'HaganD, SinghM, UgozzoliMet al.Induction of potent immune responses by cationic microparticles with adsorbed human immunodeficiency virus DNA vaccines. J Virol, 2001; 75:9037–9043.
18.
PeirisJS, LaiST, PoonLLet al.Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet, 2003; 361:1319–1325.
19.
RotaPA, ObersteMS, MonroeSSet al.Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science, 2003; 300:1394–1399.
20.
SaoulliK, LeeSY, CannonsJLet al.CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand. J Exp Med, 1998; 187:1849–1862.
21.
SatoH, MasudaM, KanaiM, Tsukiyama-KoharaK, YonedaM, KaiC. Measles virus N protein inhibits host translation by binding to eIF3-p40. J Virol, 2007; 81:11569–11576.
22.
SchirmbeckR, ZhengX, RoggendorfM, GeisslerM, ChisariFV, ReimannJ, LuM. Targeting murine immune responses to selected T cell- or antibody-defined determinants of the hepatitis B surface antigen by plasmid DNA vaccines encoding chimeric antigen. J Immunol, 2001; 166:1405–1413.
23.
SkowronskiDM, AstellC, BrunhamRCet al.Severe acute respiratory syndrome (SARS): a year in review. Annu Rev Med, 2005; 56:357–381.
24.
TykocinskiML, ShuHK, AyersDJet al.Glycolipid reanchoring of T-lymphocyte surface antigen CD8 using the 3′ end sequence of decay-accelerating factor's mRNA. Proc Natl Acad Sci USA, 1988; 85:3555–3559.
25.
WebsterRG, FynanEF, SantoroJC, RobinsonH. Protection of ferrets against influenza challenge with a DNA vaccine to the haemagglutinin. Vaccine, 1994; 12:1495–1498.
26.
WooPC, LauSK, TsoiHWet al.SARS coronavirus spike polypeptide DNA vaccine priming with recombinant spike polypeptide from Escherichia coli as booster induces high titer of neutralizing antibody against SARS coronavirus. Vaccine, 2005; 23:4959–4968.
27.
ZhengG, ChenA, SternerRE, ZhangPJ, PanT, KiyatkinN, TykocinskiML. Induction of antitumor immunity via intratumoral tetra-costimulator protein transfer. Cancer Res, 2001; 61:8127–8134.
28.
ZhengG, LiuS, WangP, XuY, ChenA. Arming tumor-reactive T cells with costimulator B7-1 enhances therapeutic efficacy of the T cells. Cancer Res, 2006; 66:6793–6799.
29.
ZhengG, WangB, ChenA. The 4-1BB costimulation augments the proliferation of CD4+ CD25+ regulatory T cells. J Immunol, 2004; 173:2428–2434.
30.
ZhuMS, PanY, ChenHQ, ShenY, WangXC, SunYJ, TaoKH. Induction of SARS-nucleoprotein-specific immune response by use of DNA vaccine. Immunol Lett, 2004; 92:237–243.
