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Tumor-specific cytotoxic T cell generation and dendritic cell function are differentially regulated by interleukin 27 during development of anti-tumor immunity.

Abstract
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.
AuthorsYukari Shinozaki, Sen Wang, Yoshiyuki Miyazaki, Kohji Miyazaki, Hisakata Yamada, Yasunobu Yoshikai, Hiromitsu Hara, Hiroki Yoshida
JournalInternational journal of cancer (Int J Cancer) Vol. 124 Issue 6 Pg. 1372-8 (Mar 15 2009) ISSN: 1097-0215 [Electronic] United States
PMID19089917 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Angiogenesis Inhibitors
  • Il27ra protein, mouse
  • Interleukin-17
  • Interleukin-2
  • RNA, Neoplasm
  • Receptors, Cytokine
  • Receptors, Interleukin
  • Ovalbumin
Topics
  • Angiogenesis Inhibitors
  • Animals
  • Dendritic Cells (immunology)
  • Interleukin-17 (immunology)
  • Interleukin-2 (immunology)
  • Melanoma (immunology)
  • Melanoma, Experimental (immunology)
  • Mice
  • Mice, Knockout
  • Neoplasms (immunology)
  • Neuroblastoma (immunology)
  • Ovalbumin (immunology)
  • RNA, Neoplasm (genetics, immunology)
  • Receptors, Cytokine (deficiency)
  • Receptors, Interleukin
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes, Cytotoxic (immunology)
  • Th1 Cells (immunology)

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