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

• Published in: PLoS pathogens Vol. 13; no. 1; p. e1006120
• Main Authors: Kinosada, Haruka, Yasunaga, Jun-ichirou, Shimura, Kazuya, Miyazato, Paola, Onishi, Chiho, Iyoda, Tomonori, Inaba, Kayo, Matsuoka, Masao
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.01.2017; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - metabolism; Biology and Life Sciences; CD3 Complex - metabolism; Cell death; Cell growth; Cell Line, Tumor; Cell Proliferation - physiology; Development and progression; Disease transmission; Encephalomyelitis, Autoimmune, Experimental - virology; Flow cytometry; Funding; Genes; GRB2 Adaptor Protein - metabolism; HTLV-I Infections - transmission; HTLV-I Infections - virology; Human T-lymphotropic virus 1 - pathogenicity; Humans; Immunology; Inflammatory diseases; Jurkat Cells; Laboratories; Leukemia; Life sciences; Lymphocyte Activation - immunology; Lymphocytes; Lymphoma; Medical research; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Non-Hodgkin's lymphomas; Physiological aspects; Physiology; Programmed Cell Death 1 Receptor - biosynthesis; Programmed Cell Death 1 Receptor - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Proteins - metabolism; R&D; Receptors, Immunologic - biosynthesis; Receptors, Immunologic - metabolism; Research & development; Research and Analysis Methods; Retroviridae; Retroviridae Proteins - genetics; Retroviridae Proteins - metabolism; Rodents; T cell receptors; T cells; T-Lymphocytes - immunology; ZAP-70 Protein-Tyrosine Kinase - metabolism; Japan
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006120

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.