Cytokines required for induction of histocompatibility leukocyte antigen-class I-restricted and tumor-specific cytotoxic T lymphocytes by a SART1-derived peptide.
Although there have been several reports on peptides of human tumor-rejection antigens capable of inducing histocompatibility leukocyte antigen (HLA)-class I-restricted and tumor-specific cytotoxic T lymphocytes (CTLs), it is not yet clear which cytokines are required for CTL induction. This study has investigated the cytokine combinations required for optimal induction of CTLs by SART1(690-698) peptide, which is capable of inducing HLA-A24-restricted and tumor-specific CTLs in peripheral blood mononuclear cells (PBMCs). Pretreatment of PBMCs as a source of antigen-presenting cells (APCs) with interferon (IFN)-gamma, or to some extent with IFN-alpha, but not with any of the other cytokines tested, augmented the peptide-induced CTL activity in HLA-A24 heterozygotes, but not in HLA-A24 homozygotes. This IFN-gamma-mediated augmentation was inhibited by either interleukin (IL)-4 or IL-10. IL-2 alone in culture, along with weekly stimulation by peptide-pulsed APCs, was sufficient for the differentiation and proliferation of CTLs for the initial several weeks of culture. This IL-2-mediated activation of CTLs was inhibited by the addition of IFN-gamma, IL-4, or IL-10 to the IL-2 culture. For further expansion of the CTLs, dendritic cells (DCs) induced from PBMCs with IL-4 and granulocyte macrophage colony-stimulating factor (GM-CSF) were required as APCs. These results indicate that IFN-gamma and IL-2 are important in the activation of APCs and CTLs, respectively, while GM-CSF and IL-4 are needed for the induction of DCs, which in turn are required for further expansion of mature CTLs. These results are important in allowing for a better understanding of the cellular and molecular basis of tumor-specific immunity, and also for the development of peptide-based specific immunotherapy.
Matsunaga
K
K
Cancer Vaccine Development Division of Kurume University Research Center for Innovative Cancer Therapy.
Nakao
M
M
Masuoka
K
K
Inoue
Y
Y
Gouhara
R
R
Imaizumi
T
T
Nishizaka
S
S
Itoh
K
K
D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000951:Antigens, Neoplasm; D016207:Cytokines / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D015234:HLA-A Antigens / Q000096:biosynthesis / Q000276:immunology*; D059871:HLA-A24 Antigen; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D009363:Neoplasm Proteins / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D017411:Ribonucleoproteins, Small Nuclear; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*
D000951:Antigens, Neoplasm; D016207:Cytokines; D015234:HLA-A Antigens; D059871:HLA-A24 Antigen; D007376:Interleukin-2; D009363:Neoplasm Proteins; D010455:Peptides; D017411:Ribonucleoproteins, Small Nuclear; C431323:SART1 protein, human; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor