IFN-alpha beta promote priming of antigen-specific CD8+ and CD4+ T lymphocytes by immunostimulatory DNA-based vaccines.
Immunostimulatory sequence (ISS) DNA containing unmethylated CpG dinucleotides stimulate NK and APC to secrete proinflammatory cytokines, including IFN-alphabeta and -gamma, TNF-alpha, and IL-6 and -12, and to express costimulatory surface molecules such as CD40, B7-1, and B7-2. Although ISS DNA has little direct effect on T cells by these criteria, immunization of wild-type mice with ISS DNA and OVA results in Ag-specific CTL and Th1-type T helper activity. This investigation examines the mechanisms by which ISS DNA primes CD8(+) and CD4(+) lymphocyte activities. In this report we demonstrate that ISS DNA regulates the expression of costimulatory molecules and TAP via a novel autocrine or paracrine IFN-alphabeta pathway. Coordinated regulation of B7 costimulation and TAP-dependent cross-presentation results in priming of Ag-specific CD8(+) CTL, whereas CD40, B7, and IL-12 costimulation is required for priming of CD4(+) Th cells by ISS-based vaccines.
Cho
Hearn Jay
HJ
Division of Hematology/Medical Oncology, Department of Medicine, New York Presbyterian Hospital and Cornell Medical Center, 525 East 68th Street, New York, NY 10021. hjc2001@med.cornell.edu
Hayashi
Tomoko
T
Datta
Sandip K
SK
Takabayashi
Kenji
K
Van Uden
John Henry
JH
Horner
Anthony
A
Corr
Maripat
M
Raz
Eyal
E
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000502:physiology; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000502:physiology; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004357:Drug Synergism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D007370:Interferon Type I / Q000502:physiology*; D018664:Interleukin-12 / Q000502:physiology; D007399:Interphase / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology; D014407:Tumor Cells, Cultured; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; C408982:CPG-oligonucleotide; C497965:Cd86 protein, mouse; D018984:Epitopes, T-Lymphocyte; D007370:Interferon Type I; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse; C489516:Tap2 protein, mouse; D019444:Vaccines, DNA; C071692:TAP2 protein, human; D018664:Interleukin-12