HTLV-1 bZIP Factor Enhances T-Cell Proliferation by Impeding the Suppressive Signaling of Co-inhibitory Receptors

Human t-cell leukemia virus type 1 (htlv-1) causes adult t-cell leukemia-lymphoma (atl) and inflammatory diseases. to enhance cell-to-cell transmission of htlv-1,the virus increases the number of infected cells in vivo. htlv-1 bzip factor (hbz) is constitutively expressed in htlv-1 infected cells and atl cells and promotes t-cell proliferation. however,the detailed mechanism by which it does so remains unknown. here,we show that hbz enhances the proliferation of expressing t cells after stimulation via the t-cell receptor. hbz promotes this proliferation by influencing the expression and function of multiple co-inhibitory receptors. hbz suppresses the expression of btla and lair-1 in hbz expressing t cells and atl cells. expression of t cell immunoglobulin and itim domain (tigit) and programmed cell death 1 (pd-1) was enhanced,but their suppressive effect on t-cell proliferation was functionally impaired. hbz inhibits the co-localization of shp-2 and pd-1 in t cells,thereby leading to impaired inhibition of t-cell proliferation and suppressed dephosphorylation of zap-70 and cd3ζ. hbz does this by interacting with themis,which associates with grb2 and shp-2. thus,hbz interacts with the shp containing complex,impedes the suppressive signal from pd-1 and tigit,and enhances the proliferation of t cells. although hbz was present in both the nucleus and the cytoplasm of t cells,hbz was localized largely in the nucleus by suppressed expression of themis by shrna. this indicates that themis is responsible for cytoplasmic localization of hbz in t cells. since themis is expressed only in t-lineage cells,hbz mediated inhibition of the suppressive effects of co-inhibitory receptors accounts for how htlv-1 induces proliferation only of t cells in vivo. this study reveals that hbz targets co-inhibitory receptors to cause the proliferation of infected cells. © 2017 kinosada et al.