タケノウチ　ノリヒロ   TAKENOUCHI NORIHIRO   竹之内　徳博    所属   関西医科大学  微生物学講座    職種   准教授
論文種別	原著(症例報告除く)
言語種別	英語
査読の有無	査読あり
表題	HTLV-1 bZIP factor impairs anti-viral immunity by inducing co-inhibitory molecule, T cell immunoglobulin and ITIM domain (TIGIT)
掲載誌名	正式名：PLoS pathogens 略　 称：PLoS Pathog ISSNコード：15537366/15537374
巻・号・頁	12(1),pp.e1005372
著者・共著者	Yasuma K, Yasunaga JI, Takemoto K, Sugata K, Mitobe Y, Takenouchi N, Nakagawa M, Suzuki Y, Matsuoka M.
発行年月	2016/01
概要	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.
DOI	10.1371/journal.ppat.1005372
文献番号	26735971
PMID	26735971