title: HTLV-1 bZIP Factor Enhances T-Cell Proliferation by Impeding the Suppressive Signaling of Co-inhibitory Receptors.
abstract: 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.
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.|Department of Mammalian Regulatory Network, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Haruka
authors.identifier: 0000-0002-8408-4138
authors.initials: H
authors.lastname: Kinosada
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Jun-Ichirou
authors.identifier: 0000-0002-7939-2080
authors.initials: JI
authors.lastname: Yasunaga
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimura
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Paola
authors.identifier: 0000-0002-4360-4029
authors.initials: P
authors.lastname: Miyazato
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Chiho
authors.initials: C
authors.lastname: Onishi
authors.affiliation: Laboratory of Immunology, Department of Animal Development and Physiology, Division of Systemic Life Science, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Iyoda
authors.affiliation: Laboratory of Immunology, Department of Animal Development and Physiology, Division of Systemic Life Science, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Inaba
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.|Department of Hematology, Rheumatology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, Japan.
authors.forename: Masao
authors.identifier: 0000-0002-0473-754X
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000821:virology; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D015490:HTLV-I Infections / Q000635:transmission* / Q000821:virology; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000378:metabolism; D012191:Retroviridae Proteins / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: C488868:BTLA protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; C479751:HBZ protein, human T-cell leukemia virus type I; D036341:Intercellular Signaling Peptides and Proteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011506:Proteins; D011971:Receptors, Immunologic; D012191:Retroviridae Proteins; C556305:T cell Ig and ITIM domain protein, mouse; C108073:leukocyte-associated immunoglobulin-like receptor 1; C544192:themis protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse