HTLV-1 bZIP Factor Impairs Anti-viral Immunity by Inducing Co-inhibitory Molecule, T Cell Immunoglobulin and ITIM Domain (TIGIT)

• 安永, 純一朗

• 松岡, 雅雄

• Takemoto, Keiko

• Sugata, Kenji

• Mitobe, Yuichi

• Takenouchi, Norihiro

• Nakagawa, Masanori

• Suzuki, Yutaka

• Matsuoka, Masao

• Susan R Ross

  editor

抄録

Human T-cell leukemia virus type 1 (HTLV-1) infects CD4+ T cells and induces proliferation of infected cells in vivo, which leads to the onset of adult T-cell leukemia (ATL) in some infected individuals. The HTLV-1 bZIP factor (HBZ) gene, which is encoded in the minus strand of HTLV-1, plays critical roles in pathogenesis. In this study, RNA-seq and ChIP-seq analyses using HBZ transduced T cells revealed that HBZ upregulates the expression and promoter acetylation levels of a co-inhibitory molecule, T cell immunoglobulin and ITIM domain (TIGIT), in addition to those of regulatory T cells related genes, Foxp3 and Ccr4. TIGIT was expressed on CD4+ T cells from HBZ-transgenic (HBZ-Tg) mice, and on ATL cells and HTLV-1 infected CD4+ T cells of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in vivo. Expression of Blimp1 and IL-10 was upregulated in TIGIT+CD4+ cells of HBZ-Tg mice compared with TIGIT-CD4+ T cells, suggesting the correlation between TIGIT expression and IL-10 production. When CD4+ T cells from HBZ-Tg mice were stimulated with TIGIT’s ligand, CD155, their production of the inhibitory cytokine IL-10 was enhanced. Furthermore, dendritic cells from HBZ-Tg mice produced high levels of IL-10 after stimulation. These data suggest that HBZ alters immune system to suppressive state via TIGIT and IL-10. Importantly, TIGIT suppressed T-cell responses to another HTLV-1 virus protein, Tax, in vitro. Blocking of TIGIT and PD-1 slightly increased anti-Tax T-cell activity in some HAM/TSP patients. These results suggest that HBZ-induced TIGIT on HTLV-1 infected cells impairs T-cell responses to viral antigens. This study shows that HBZ-induced TIGIT plays a pivotal role in attenuating host immune responses and shaping a microenvironment favorable to HTLV-1.

収録刊行物

• PLOS Pathogens

  PLOS Pathogens 12 (1), e1005372-, 2016-01-06

  Public Library of Science

キーワード

• Virology
• Genetics
• Molecular Biology
• Immunology
• Microbiology
• Parasitology

詳細情報

• CRID: 1050564285786400512
• NII論文ID: 120005763385
• ISSN: 15537374
• DOI: 10.1371/journal.ppat.1005372
• HANDLE: 2433/214493
• Web Site: http://dx.plos.org/10.1371/journal.ppat.1005372
• 本文言語コード: en
• 資料種別: journal article
• データソース種別:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN