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HTLV-1 bZIP Factor Enhances T-Cell Proliferation by Impeding the Suppressive Signaling of Co-inhibitory Receptors.
- Source :
-
PLoS pathogens [PLoS Pathog] 2017 Jan 03; Vol. 13 (1), pp. e1006120. Date of Electronic Publication: 2017 Jan 03 (Print Publication: 2017). - Publication Year :
- 2017
-
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 CD3ΞΆ. 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.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Animals
Basic-Leucine Zipper Transcription Factors genetics
CD3 Complex metabolism
Cell Line, Tumor
Encephalomyelitis, Autoimmune, Experimental virology
GRB2 Adaptor Protein metabolism
HTLV-I Infections virology
Humans
Intercellular Signaling Peptides and Proteins
Jurkat Cells
Lymphocyte Activation immunology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Programmed Cell Death 1 Receptor biosynthesis
Programmed Cell Death 1 Receptor metabolism
Protein Tyrosine Phosphatase, Non-Receptor Type 11 metabolism
Receptors, Immunologic biosynthesis
Receptors, Immunologic metabolism
Retroviridae Proteins genetics
ZAP-70 Protein-Tyrosine Kinase metabolism
Basic-Leucine Zipper Transcription Factors metabolism
Cell Proliferation physiology
HTLV-I Infections transmission
Human T-lymphotropic virus 1 pathogenicity
Proteins metabolism
Retroviridae Proteins metabolism
T-Lymphocytes immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7374
- Volume :
- 13
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- PLoS pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 28046066
- Full Text :
- https://doi.org/10.1371/journal.ppat.1006120