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

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. © 2016 yasuma et al.