title: CD4+ TH1 cells generated by Ii-PADRE DNA at prime phase are important to induce effectors and memory CD8+ T cells.
abstract: 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.
authors.affiliation: Department of Anatomy, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jae Yeo
authors.initials: JY
authors.lastname: Park
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Jin
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Lee
authors.forename: Min Ja
authors.initials: MJ
authors.lastname: Jang
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Hyo Seon
authors.initials: HS
authors.lastname: Shin
authors.forename: Yoon Hee
authors.initials: YH
authors.lastname: Chung
authors.forename: Kyung Yong
authors.initials: KY
authors.lastname: Kim
authors.forename: Sung Su
authors.initials: SS
authors.lastname: Kim
authors.forename: Won Bok
authors.initials: WB
authors.lastname: Lee
authors.forename: Yong Kyoo
authors.initials: YK
authors.lastname: Shin
authors.forename: Wang Jae
authors.initials: WJ
authors.lastname: Lee
authors.forename: Yeong-Min
authors.initials: YM
authors.lastname: Park
authors.forename: Daejin
authors.initials: D
authors.lastname: Kim
mesh_terms: 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
chemical_list: 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