title: HTLV-1 bZIP Factor Impairs Anti-viral Immunity by Inducing Co-inhibitory Molecule, T Cell Immunoglobulin and ITIM Domain (TIGIT).
abstract: 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.
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Yasuma
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Jun-ichirou
authors.initials: J
authors.lastname: Yasunaga
authors.affiliation: Laboratory of Biological Protection, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Takemoto
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugata
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Mitobe
authors.affiliation: Department of Microbiology, Kansai Medical University, Hirakata, Osaka, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Takenouchi
authors.affiliation: North Medical Center, Kyoto Prefectural University of Medicine, Yosano-cho, Kyoto, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Computational Biology and Medical Science, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D015368:Human T-lymphotropic virus 1 / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D011971:Receptors, Immunologic / Q000276:immunology*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D011971:Receptors, Immunologic; C556305:T cell Ig and ITIM domain protein, mouse; C534712:TIGIT protein, human