Search results

The requirement for CD4(+) T cells in priming and maintaining cytotoxic T-lymphocyte responses presents a long-standing paradox in cellular immunology. In this study, we used sequential coadministration of a DNA vaccine encoding an invariant (Ii) chain in which the class II-associated Ii-peptide region is replaced with CD4(+) T-helper epitope, PADRE [Pan human leukocyte antigen-DR reactive epitope (Ii-PADRE)] or BclxL with a DNA vaccine encoding Sig/E7/LAMP-1 to verify the role of CD4(+) T cells for the generation of effectors and memory E7-specific CD8(+) T-cell immune responses. Sequential vaccination, with Ii-PADRE + Sig/E7/LAMP-1 priming followed by BclxL + Sig/E7/LAMP-1 boosting led to generation of E7-specific CD8(+) T cells, and was nearly equivalent in effect to coadministration with Ii-PADRE+Sig/E7/LAMP-1 or Bcl-xL + Sig/E7/LAMP-1 at both prime and boost. The mice vaccinated with the Ii-PADRE+Sig/E7/LAMP-1 prime-Bcl-xL + Sig/E7/LAMP-1 boost regimen exhibited better long-term E7-specific immune responses and tumor prevention effects in vivo than the mice vaccinated with the reverse sequential coadministration. After CD4+ T-cell depletion, mice primed with Ii-PADRE+Sig/E7/LAMP-1 generated low numbers of E7-specific CD8(+) T cells and suppressed long-term memory CD8(+) T-cell response regardless of the sequence or combination of DNA vaccines administered. Mice primed with Bcl-xL + Sig/E7/LAMP-1 only suppressed long-term memory CD8(+) T-cell response after depletion of CD4(+) T cells before priming. Our findings suggest that activated CD4(+) T cells at prime phase are important to generate the antigen-specific CD8(+) T-cell immune responses and CD4(+) T cells, which are naive or activated, play a role to maintain the long-term memory responses. ; Supported by the Korea Research Foundation Grant funded by the Korean Government (KRF-2008-314-E00195). ; Kim D, 2008, GENE THER, V15, P677, DOI 10.1038/sj.gt.3303102 ; Kim DJ, 2007, HUM GENE THER, V18, P1129, DOI 10.1089/hum.2007.090 ; Hung CF, 2007, MOL THER, V15, P1211, DOI 10.1038/sj.mt.6300121 ; Tsen SWD, 2007, EXPERT REV VACCINES, V6, P227, DOI 10.1586/14760584.6.2.227 ; Mueller SN, 2006, J IMMUNOL, V176, P7379 ; Castellino F, 2006, ANNU REV IMMUNOL, V24, P519, DOI 10.1146/annurev.immunol.23.021704.115825 ; HUNG CF, 2006, METH MOLEC MED, V127, P199 ; Peng SW, 2004, J VIROL, V78, P8468, DOI 10.1128/JVI.78.16.8468-8476.2004 ; Fujii SI, 2004, J EXP MED, V199, P1607, DOI 10.1084/jem.20040317 ; Behrens GMN, 2004, J IMMUNOL, V172, P5420 ; Lin CT, 2003, MOL THER, V8, P559, DOI 10.1016/S1525-0016(03)00238-7 ; Kim TW, 2003, J IMMUNOL, V171, P2970 ; Kim TW, 2003, J CLIN INVEST, V112, P109, DOI 10.1172/JCI200317293 ; Janssen EM, 2003, NATURE, V421, P852, DOI 10.1038/nature01441 ; Ouaaz F, 2002, IMMUNITY, V16, P257 ; Medema JP, 2001, J EXP MED, V194, P657 ; den Boer AT, 2001, J IMMUNOL, V167, P2522 ; Allen TM, 2000, J IMMUNOL, V164, P4968 ; Chen CH, 2000, CANCER RES, V60, P1035 ; Josien R, 2000, J EXP MED, V191, P495 ; Gurunathan S, 2000, ANNU REV IMMUNOL, V18, P927, DOI 10.1146/annurev.immunol.18.1.927 ; Ji HX, 1999, HUM GENE THER, V10, P2727 ; Kent SJ, 1998, J VIROL, V72, P10180 ; Klenerman P, 1998, NATURE, V394, P482 ; McMichael AJ, 1998, NATURE, V394, P421 ; Irvine KR, 1997, J NATL CANCER I, V89, P1595 ; Jaiswal AI, 1997, J IMMUNOL, V159, P2282 ; DONNELLY JJ, 1997, LIFE SCI, V60, P163 ; Cella M, 1996, J EXP MED, V184, P747 ; Lin KY, 1996, CANCER RES, V56, P21 ; KEENE JA, 1982, J EXP MED, V155, P768 ; 0