ArticlePLoS pathogens2017
HTLV-1 bZIP Factor Enhances T-Cell Proliferation by Impeding the Suppressive Signaling of Co-inhibitory Receptors.
Article in PLoS pathogens, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 41 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
41 citing papers in PubMed, 64 citations in OpenAlex.
- Phase II Study of the PD-1 Inhibitor Pembrolizumab for the Treatment of Relapsed or Refractory Mature T-cell Lymphoma.Clinical lymphoma, myeloma & leukemia · 2019Trial
- Intra-pol proviral open region of HTLV-1 controls the transcription from both long terminal repeats.Retrovirology · 2025Article
- JunB-HBZ nuclear translocation by TGF-β is a key driver in HTLV-1-mediated leukemogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Identification of iron metabolism-related key genes and exploration of their potential mechanisms in hemophagocytic lymphohistiocytosis based on transcriptome sequencing.Frontiers in medicine · 2025Article
- Development of Innate-Immune-Cell-Based Immunotherapy for Adult T-Cell Leukemia-Lymphoma.Cells · 2024Article
- Themis controls T cell activation, effector functions, and metabolism of peripheral CD8Life science alliance · 2023Article
- Understanding the Immunopathology of HTLV-1-Associated Adult T-Cell Leukemia/Lymphoma: A Comprehensive Review.Biomolecules · 2023Review
- HTLV-1 bZIP Factor-Induced Reprogramming of Lactate Metabolism and Epigenetic Status Promote Leukemic Cell Expansion.Blood cancer discovery · 2023Article
- Mouse Models for HTLV-1 Infection and Adult T Cell Leukemia.International journal of molecular sciences · 2023Review
- Retroviral b-Zip protein (HBZ) contributes to the release of soluble and exosomal immune checkpoint molecules in the context of neuroinflammation.Journal of extracellular biology · 2023Article
- THEMIS increases TCR signaling in CD4Science signaling · 2023Article
- Can Soluble Immune Checkpoint Molecules on Exosomes Mediate Inflammation?Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2022Review
- Negative times negative equals positive, THEMIS sets the rule on thymic selection and peripheral T cell responses.Biomedical journal · 2022Review
- A newly identified interaction between nucleolar NPM1/B23 and the HTLV-I basic leucine zipper factor in HTLV-1 infected cells.Frontiers in microbiology · 2022Article
- HTLV-1 persistence and leukemogenesis: A game of hide-and-seek with the host immune system.Frontiers in immunology · 2022Review
- The Road to HTLV-1-Induced Leukemia by Following the Subcellular Localization of HTLV-1-Encoded HBZ Protein.Frontiers in immunology · 2022Review
- Functional and Pathogenic Roles of Retroviral Antisense Transcripts.Frontiers in immunology · 2022Review
- Is it NICE (nuclear import as a carcinogenic mechanism) to restrict HBZ in the cytoplasm?Haematologica · 2021Article
- Dual cytoplasmic and nuclear localization of HTLV-1-encoded HBZ protein is a unique feature of adult T-cell leukemia.Haematologica · 2021Article
- Human T-cell lymphotropic virus HBZ and tax mRNA expression are associated with specific clinicopathological features in adult T-cell leukemia/lymphoma.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2021Article
Corrections and comments
- Erratum issued
Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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