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

Haruka Kinosada; Jun-Ichirou Yasunaga; Kazuya Shimura; Paola Miyazato; Chiho Onishi; Tomonori Iyoda; Kayo Inaba; Masao Matsuoka

doi:10.1371/journal.ppat.1006120

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

PLoS Pathog. 2017 Jan 3;13(1):e1006120. doi: 10.1371/journal.ppat.1006120. eCollection 2017 Jan.

Authors

Haruka Kinosada^{1

2}, Jun-Ichirou Yasunaga¹, Kazuya Shimura¹, Paola Miyazato¹, Chiho Onishi¹, Tomonori Iyoda³, Kayo Inaba³, Masao Matsuoka^{1

4}

Affiliations

¹ Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
² Department of Mammalian Regulatory Network, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, Japan.
³ Laboratory of Immunology, Department of Animal Development and Physiology, Division of Systemic Life Science, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, Japan.
⁴ Department of Hematology, Rheumatology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, Japan.

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.

MeSH terms

Animals
Basic-Leucine Zipper Transcription Factors / genetics
Basic-Leucine Zipper Transcription Factors / metabolism*
CD3 Complex / metabolism
Cell Line, Tumor
Cell Proliferation / physiology*
Encephalomyelitis, Autoimmune, Experimental / virology
GRB2 Adaptor Protein / metabolism
HTLV-I Infections / transmission*
HTLV-I Infections / virology
Human T-lymphotropic virus 1 / pathogenicity*
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
Proteins / metabolism*
Receptors, Immunologic / biosynthesis
Receptors, Immunologic / metabolism
Retroviridae Proteins / genetics
Retroviridae Proteins / metabolism*
T-Lymphocytes / immunology*
ZAP-70 Protein-Tyrosine Kinase / metabolism

Substances

BTLA protein, mouse
Basic-Leucine Zipper Transcription Factors
CD3 Complex
CD3 antigen, zeta chain
GRB2 Adaptor Protein
Grb2 protein, mouse
HBZ protein, human T-cell leukemia virus type I
Intercellular Signaling Peptides and Proteins
Pdcd1 protein, mouse
Programmed Cell Death 1 Receptor
Proteins
Receptors, Immunologic
Retroviridae Proteins
T cell Ig and ITIM domain protein, mouse
leukocyte-associated immunoglobulin-like receptor 1
themis protein, mouse
ZAP-70 Protein-Tyrosine Kinase
Zap70 protein, mouse
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Ptpn11 protein, mouse

Grants and funding

This research is supported by the Project for Cancer Research And Therapeutic Evolution (P-CREATE) from Japan Agency for Medical Research and development, AMED, and by JSPS KAKENHI Grant Numbers JP16H05336 (MM), JP26460554 (JY) and JP16J08048 (HK), and a grant from Mitsubishi Foundation (MM). This study was also supported in part by the JSPS Core-to-Core Program A, Advanced Research Networks. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.