CD4+ TH1 cells generated by Ii-PADRE DNA at prime phase are important to induce effectors and memory CD8+ T cells.
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 Bcl-xL 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 Bcl-xL+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.
Park
Jae Yeo
JY
Department of Anatomy, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
Jin
Dong-Hoon
DH
Lee
Chang-Min
CM
Jang
Min Ja
MJ
Lee
Sun Young
SY
Shin
Hyo Seon
HS
Chung
Yoon Hee
YH
Kim
Kyung Yong
KY
Kim
Sung Su
SS
Lee
Won Bok
WB
Shin
Yong Kyoo
YK
Lee
Wang Jae
WJ
Park
Yeong-Min
YM
Kim
Daejin
D
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019496:Cancer Vaccines; D002450:Cell Communication; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007117:Immunization, Secondary; D007156:Immunologic Memory / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D008212:Lymphocyte Depletion; D017780:Malaria Vaccines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000276:immunology; D051020:bcl-X Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D000944:Antigens, Differentiation, B-Lymphocyte; D019496:Cancer Vaccines; D000949:Histocompatibility Antigens Class II; D017780:Malaria Vaccines; C401223:PADRE 45; D050725:Papillomavirus E7 Proteins; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D051020:bcl-X Protein; C045084:invariant chain