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

PLoS Pathogens

Yutaka Suzuki¹  Norihiro Takenouchi²  Keiko Takemoto³  Jun-ichirou Yasunaga⁴  Kenji Sugata⁴  Yuichi Mitobe⁴  Masao Matsuoka⁴  Keiko Yasuma⁴  Masanori Nakagawa⁵ 

[1] Department of Computational Biology and Medical Science, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan;Department of Microbiology, Kansai Medical University, Hirakata, Osaka, Japan;Laboratory of Biological Protection, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan;Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan;North Medical Center, Kyoto Prefectural University of Medicine, Yosano-cho, Kyoto, Japan

关键词: T cells;    HTLV-1;    Immune response;    Antibodies;    Enzyme-linked immunoassays;    DNA transcription;    Cytotoxic T cells;    Regulatory T cells;   

DOI  :  10.1371/journal.ppat.1005372

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY