Selective induction of high avidity CTL by altering the balance of signals from APC.
High avidity CTL are most effective at clearing viruses and cancer cells. Therefore, understanding the mechanisms involved in induction of high avidity CTL is critical for effective vaccines. However, no vaccine approach to selectively induce high avidity CTL in vivo has been discovered. In a new approach, signals from MHC class I (signal 1) and costimulatory molecules (signal 2) were adjusted by varying Ag dose and by use of recombinant poxvirus expressing a triad of costimulatory molecules (B7-1, ICAM-1, and LFA-3), respectively. Independent of CTL avidity, a strong signal 1 resulted in an increased frequency of CD8(+) CTL. However, a strong signal 2 was necessary for the induction of high avidity CD8(+) CTL that killed target cells more efficiently, and signal 2 played a more crucial role in the absence of a strong signal 1. Only CTL induced with strong signal 2 killed tumor cells endogenously expressing low levels of Ag. Signal 2 contributed to the induction of high avidity CD8(+) CTL in both primary and secondary responses. Thus, although signal 2 has been known to increase the quantity of CTL response, in this study we show that it also improves the quality of CTL response. Our data also suggested that dendritic cells play an important role in induction of high avidity CD8(+) CTL in vivo. This strategy to selectively induce higher avidity CTL may lead to more effective vaccines for viruses and cancer.
Oh
SangKon
S
Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Hodge
James W
JW
Ahlers
Jeffrey D
JD
Burke
Donald S
DS
Schlom
Jeffrey
J
Berzofsky
Jay A
JA
D016475:3T3 Cells; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology; D018968:CD58 Antigens / Q000235:genetics / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation / Q000821:virology; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000032:analysis; D005260:Female; D006801:Humans; D007117:Immunization, Secondary; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D011212:Poxviridae / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014614:Vaccines, Synthetic / Q000235:genetics / Q000494:pharmacology
D018122:B7-1 Antigen; D018968:CD58 Antigens; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D010455:Peptides; D014614:Vaccines, Synthetic; C439566:rV-Tricom; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma