Tumor-specific cytotoxic T cell generation and dendritic cell function are differentially regulated by interleukin 27 during development of anti-tumor immunity.
Interleukin (IL-) 27 is a member of IL-12 cytokine family with Th1-promoting and anti-inflammatory effects. IL-27 has been shown to facilitate tumor-specific cytotoxic T lymphocyte (CTL) induction against various tumors. However, IL-27 suppresses cytokine production of lymphocytes and antigen-presenting function of dendritic cells (DCs). To examine the in vivo role of IL-27 in generation of anti-tumor immunity, we examined IL-27-mediated antitumor-effects using WSX-1 (IL-27 receptor alpha chain)-deficient (WSX-1(-/-)) mice. In WSX-1(-/-) mice inoculated with B16 melanoma cells, tumor growth was higher than in wild-type (WT) mice. Accordingly, tumor-specific CTL generation was lower in WSX-1(-/-) mice than in WT mice. CTL induction in WSX-1(-/-) mice was not restored by transfer of WT DCs pulsed with TRP2 peptide, indicating that IL-27 is directly required for generation of tumor-specific CTLs. However, when transferred into tumor-bearing mice, WSX-1(-/-) DCs pulsed with TRP2 peptide was more potent than WT DCs in tumor growth inhibition and generation of CTLs, indicating suppressive effects of IL-27 on DC function. Finally, the combination of WT CD8(+) T cells and KO DCs is more potent in generation of antigen-specific CTLs than any other combinations. Expression of perforin gene and percentages of tumor-specific CD8(+) T cells were also the highest in the combination of WT CD8+ T cells and WSX-1(-/-) DCs. It was thus revealed that IL-27 promotes CTL generation while suppressing DC function during generation of tumor immunity. The combination of WT T cells and IL-27 signal-defective DCs may have therapeutic potential against tumors.
Shinozaki
Yukari
Y
Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan.
Wang
Sen
S
Miyazaki
Yoshiyuki
Y
Miyazaki
Kohji
K
Yamada
Hisakata
H
Yoshikai
Yasunobu
Y
Hara
Hiromitsu
H
Yoshida
Hiroki
H
D020533:Angiogenesis Inhibitors; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology; D008545:Melanoma / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology*; D009447:Neuroblastoma / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D012334:RNA, Neoplasm / Q000235:genetics / Q000276:immunology; D018121:Receptors, Cytokine / Q000172:deficiency; D018123:Receptors, Interleukin; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
D020533:Angiogenesis Inhibitors; C484747:Il27ra protein, mouse; D020381:Interleukin-17; D007376:Interleukin-2; D012334:RNA, Neoplasm; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D010047:Ovalbumin