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| 1.
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Tanaka, Yuetsu ; Tanaka, Reiko ; Imaizumi, Naoki ; Mizuguchi, Mariko ; Takahashi, Yoshiaki ; Hayashi, Masaki ; Miyagi, Takashi ; Uchihara, Junnosuke ; Ohshiro, Kazuiku ; Masuzaki, Hiroaki ; Fukushima, Takuya
概要:
Human T-cell leukemia virus type-1 (HTLV-1) establishes a long-term persistent infection in humans and causes malignant
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T-cell leukemia, adult T-cell leukemia (ATL). HTLV-1-specific cytotoxic T lymphocytes have been suggested to play a major role in the immunosurveillance of HTLV-1-infected T cells. However, it remains unclear whether HTLV-1-specific functional antibodies are also involved in the host defense. To explore the role of antibodies in the course of HTLV-1 infection, we quantitated HTLV-1-specific neutralizing and antibody-dependent cellular cytotoxicity (ADCC)-inducing antibody levels in plasma from asymptomatic carriers (ACs) and ATL patients. The levels of neutralizing antibodies, as determined by a syncytium inhibition assay, were significantly lower in acute and chronic ATL patients than in ACs. The levels of ADCC-inducing activity were tested using an autologous pair of HTLV-1-producing cells and cultured natural killer (NK) cells, which showed that the ADCC-inducing activity of IgG at a concentration of 100 μg/ml was comparable between ACs and acute ATL patients. The anti-gp46 antibody IgG levels, determined by ELISA, correlated with those of the neutralizing and ADCC-inducing antibodies. In contrast, the proviral loads did not correlate with any of these antibody levels. NK cells and a monoclonal anti-gp46 antibody reduced the number of HTLV-1 Tax-expressing cells in cultured peripheral blood mononuclear cells from patients with aggressive ATL. These results suggest a protective role for HTLV-1 neutralizing and ADCC-inducing antibodies during the course of HTLV-1 infection.
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| 2.
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Naito, Tadasuke ; Ushirogawa, Hiroshi ; Fukushima, Takuya ; Tanaka, Yuetsu ; Saito, Mineki
概要:
Background: EOS plays an important role in maintaining the suppressive function of regulatory T cells (Tregs), and induc
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es a regulated transformation of Tregs into T helper-like cells, which are capable of secreting proinflammatory cytokines in response to specific inflammatory signals. Meanwhile, significant reduction in Treg activity along with production of proinflammatory cytokines has been reported in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).\nMethods: In this study, to examine whether there is an alteration in EOS expression in peripheral blood mononuclear cells (PBMCs) derived from HTLV-1-infected individuals especially HAM/TSP, we investigated the expression of HTLV-1 tax genotype, proviral load (PVL), and the mRNA expression of tax, HBZ and EOS in HTLV-1 infected individuals including adult T-cell leukemia/lymphoma (ATL), HAM/TSP, or asymptomatic carriers. The expression levels of EOS mRNA and protein in various HTLV-1-infected or uninfected human T-cell lines were also investigated.\nResults: EOS was highly expressed at the protein level in most HTLV-1 infected T-cell lines, and was augmented after the HTLV-1 regulatory factor Tax was induced in a Tax-inducible JPX-9 cell line. Immunoprecipitation experiments demonstrated a physical interaction between EOS and the viral regulatory protein Tax, but not HBZ. Meanwhile, there was a significant decrease in EOS mRNA levels in PBMCs of HTLV-1 infected individuals irrespective of their clinical statuses. We found an inverse correlation between EOS mRNA levels and HTLV-1 PVL in ATL patients, and positive correlations between both EOS mRNA load and PVL, and EOS and HBZ mRNA load in HAM/TSP patients, whereas this correlation was not observed in other clinical statuses.\nConclusions: These findings suggest that both Tax and HBZ can alter the expression of EOS through undetermined mechanisms, and dysregulated expression of EOS in PBMCs of HTLV-1 infected individuals may contribute to the pathological progression of HTLV-1-associated diseases, such as ATL and HAM/TSP.
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| 3.
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3. Epigenetic changes around the pX region and spontaneous HTLV-1 transcription are CTCF-independent
Miura, Michi ; Miyazato, Paola ; Satou, Yorifumi ; Tanaka, Yuetsu ; Bangham, Charles R.M.
概要:
Background: The human retrovirus HTLV-1 inserts the viral complementary DNA of 9 kb into the host genome. Both plus- and
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minus-strands of the provirus are transcribed, respectively from the 5′ and 3′ long terminal repeats (LTR). Plus-strand expression is rapid and intense once activated, whereas the minus-strand is transcribed at a lower, more constant level. To identify how HTLV-1 transcription is regulated, we investigated the epigenetic modifications associated with the onset of spontaneous plus-strand expression and the potential impact of the host factor CTCF.\nMethods: Patient-derived peripheral blood mononuclear cells (PBMCs) and in vitro HTLV-1-infected T cell clones were examined. Cells were stained for the plus-strand-encoded viral protein Tax, and sorted into Tax+ and Tax– populations. Chromatin immunoprecipitation and methylated DNA immunoprecipitation were performed to identify epigenetic modifications in the provirus. Bisulfite-treated DNA fragments from the HTLV-1 LTRs were sequenced. Single-molecule RNA-FISH was performed, targeting HTLV-1 transcripts, for the estimation of transcription kinetics. The CRISPR/Cas9 technique was applied to alter the CTCF-binding site in the provirus, to test the impact of CTCF on the epigenetic modifications.\nResults: Changes in the histone modifications H3K4me3, H3K9Ac and H3K27Ac were strongly correlated with plus-strand expression. DNA in the body of the provirus was largely methylated except for the pX and 3′ LTR regions, regardless of Tax expression. The plus-strand promoter was hypomethylated when Tax was expressed. Removal of CTCF had no discernible impact on the viral transcription or epigenetic modifications.\nConclusions: The histone modifications H3K4me3, H3K9Ac and H3K27Ac are highly dynamic in the HTLV-1 provirus: they show rapid change with the onset of Tax expression, and are reversible. The HTLV-1 provirus has an intrinsic pattern of epigenetic modifications that is independent of both the provirus insertion site and the chromatin architectural protein CTCF which binds to the HTLV-1 provirus.
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| 4.
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Naito, Tadasuke ; Yasunaga, Jun-ichirou ; Mitobe, Yuichi ; Shirai, Kazumasa ; Sejima, Hiroe ; Ushirogawa, Hiroshi ; Tanaka, Yuetsu ; Nakamura, Tatsufumi ; Hanada, Kousuke ; Fujii, Masahiro ; Matsuoka, Masao ; Saito, Mineki
概要:
Background: Among human T cell leukemia virus type 1 (HTLV-1)-infected individuals, there is an association between HTLV
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-1 tax subgroups (subgroup-A or subgroup-B) and the risk of HAM/TSP in the Japanese population. To investigate the role of HTLV-1 subgroups in viral pathogenesis, we studied the functional diference in the subgroupspecifc viral transcriptional regulators Tax and HBZ using microarray analysis, reporter gene assays, and evaluation of viral-host protein–protein interaction. Results: (1) Transcriptional changes in Jurkat Tet-On human T-cells that express each subgroup of Tax or HBZ protein under the control of an inducible promoter revealed diferent target gene profles; (2) the number of diferentially regulated genes induced by HBZ was 2–3 times higher than that induced by Tax; (3) Tax and HBZ induced the expres‑ sion of diferent classes of non-coding RNAs (ncRNAs); (4) the chemokine CXCL10, which has been proposed as a prognostic biomarker for HAM/TSP, was more efciently induced by subgroup-A Tax (Tax-A) than subgroup-B Tax (Tax-B), in vitro as well as in unmanipulated (ex vivo) PBMCs obtained from HAM/TSP patients; (5) reporter gene assays indicated that although transient Tax expression in an HTLV-1-negative human T-cell line activated the CXCL10 gene promoter through the NF-κB pathway, there was no diference in the ability of each subgroup of Tax to activate the CXCL10 promoter; however, (6) chromatin immunoprecipitation assays showed that the ternary complex containing Tax-A is more efciently recruited onto the promoter region of CXCL10, which contains two NF-κB binding sites, than that containing Tax-B. Conclusions: Our results indicate that diferent HTLV-1 subgroups are characterized by diferent patterns of host gene expression. Diferential expression of pathogenesis-related genes by subgroup-specifc Tax or HBZ may be asso‑ ciated with the onset of HAM/TSP.
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| 5.
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Saito, Mineki ; Sejima, Hiroe ; Naito, Tadasuke ; Ushirogawa, Hiroshi ; Matsuzaki, Toshio ; Matsuura, Eiji ; Tanaka, Yuetsu ; Nakamura, Tatsufumi ; Takashima, Hiroshi
概要:
Background:Chemokine (C-C motif) ligand 1 (CCL1) is produced by activated monocytes/ macrophages and T-lymphocytes, and
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acts as a potent attractant for Th2 cells and a subset of T-regulatory (Treg) cells. Previous reports have indicated that CCL1 is overexpressed in adult T-cell leukemia cells, mediating an autocrine anti-apoptotic loop. Because CCL1 is also known as a potent chemoattractant that plays a major role in inflammatory processes, we investigated the role of CCL1 in the pathogenesis of human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Results:The results showed that: (1) CCL1 was preferentially expressed in HAM/TSP-derived HTLV-1-infected T-cell lines, (2) CCL1 expression was induced along with Tax expression in the Tax-inducible T-cell line JPX9, (3) transient Tax expression in an HTLV-1-negative T-cell line activated the CCL1 gene promoter, (4) plasma levels of CCL1 were significantly higher in patients with HAM/TSP than in HTLV-1-seronegative patients with multiple sclerosis and HTLV-1-infected asymptomatic healthy carriers, and (5) minocycline inhibited the production of CCL1 in HTLV-1-infected T-cell lines. Conclusions:The present results suggest that elevated CCL1 levels may be associated with the pathogenesis of HAM/TSP. Although further studies are required to determine the in vivo significance, minocycline may be considered as a potential candidate for the long-term treatment of HAM/TSP via its anti-inflammatory effects, which includes the inhibition of CCL1 expression.
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| 6.
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Shiohama, Yasuo ; Naito, Tadasuke ; Matsuzaki, Toshio ; Tanaka, Reiko ; Tomoyose, Takeaki ; Takashima, Hiroshi ; Fukushima, Takuya ; Tanaka, Yuetsu ; Saito, Mineki
概要:
Background:Detection of specific immune responses against cancer/testis antigen NY-ESO-1 was recently reported in patien
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ts with adult T-cell leukemia/lymphoma (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-infected asymptomatic carriers (ACs). However, the relationship of the responses with the HTLV-1 proviral load (PVL) and the levels of viral gene expression remain unclear. Findings:We measured plasma levels of autoantibodies to NY-ESO-1 immunogenic tumor antigen in HTLV-1-infected individuals with different clinical status, and in healthy controls. Data were compared to tax and HBZ mRNA levels, and PVL. Plasma anti-NY-ESO-1 antibody was detectable in 13.7% (7/51) of ACs, 29.2% (38/130) of patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), and 18.9% (10/53) of patients with ATL. Anti-NY-ESO-1 plasma levels were significantly higher in patients with HAM/TSP than in patients with ATL or ACs. Anti-NY-ESO-1 levels were not associated with PVL or the expression levels of tax and HBZ mRNA among HTLV-1-infected individuals, regardless of clinical status. Conclusions:The present results indicate the strong humoral immune response against NY-ESO-1 in natural HTLV-1 infection, irrespective of the clinical status. The higher immunoreactivity against NY-ESO-1 is not simply associated with the levels of both HTLV-1 gene expression and the number of infected cells in vivo. Rather, it might reflect chronic and generalized immune activation in infected individuals.
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| 7.
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Shiohama, Yasuo ; Naito, Tadasuke ; Matsuzaki, Toshio ; Tanaka, Reiko ; Tomoyose, Takeaki ; Takashima, Hiroshi ; Fukushima, Takuya ; Tanaka, Yuetsu ; Saito, Mineki
概要:
Background: Human T cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ), which is encoded by a minus s
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trand mRNA, is thought to play important roles in the development of adult T-cell leukemia (ATL) and HTLV1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, a comprehensive analysis of HBZ, including mRNA and protein expression, humoral immunoreactivity against HBZ, and HTLV-1 proviral load (PVL), in HTLV1-infected individuals with different clinical status has not been reported previously. Results: In this study, using novel monoclonal antibody-based in-house enzyme-linked immunosorbent assay systems, we report the absolute quantification of HBZ protein and its plasma antibody in clinical samples from HTLV-1-infected individuals with different clinical status. The data were compared to both HBZ mRNA levels and PVL. The results showed that plasma anti-HBZ antibody was detectable only in 10.4 % (5/48) of asymptomatic carriers (ACs), 10.8 % (13/120) of HAM/TSP patients, and 16.7 % (7/42) of ATL patients. HBZ protein was detected in three out of five patients with acute ATL, but was not detected in patients with HAM/TSP (0/10) or ACs (0/4). Thus, an antibody response to HBZ was not associated with the PVL or the expression of HBZ (both at the mRNA and protein levels) or the clinical status of the infection. Conclusions: The present results emphasize the extremely low expression and immunogenicity of HBZ in natural HTLV-1 infection. However, there is a possibility that the low but distinct expression of HBZ protein in PBMCs is associated with the survival of HTLV-1-infected cells and the development of ATL.
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| 8.
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Takachi, Takayuki ; Takahashi, Masahiko ; Takahashi-Yoshita, Manami ; Higuchi, Masaya ; Obata, Miki ; Mishima, Yukio ; Okuda, Shujiro ; Tanaka, Yuetsu ; Matsuoka, Masao ; Saitoh, Akihiro ; Green, Patrick L. ; Fuji, Masahiro
概要:
Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia (ATL), which is an aggress
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ive form of T-cell malignancy. HTLV-1 oncoproteins, Tax and HBZ, play crucial roles in the immortalization of T-cells and/or leukemogenesis by dysregulating the cellular functions in the host. Recent studies show that HTLV-1-infected T-cells have reduced expression of the BCL11B tumor suppressor protein. In the present study, we explored whether Tax and/or HBZ play a role in downregulating BCL11B in HTLV-1-infected T-cells. Lentiviral transduction of Tax in a human T-cell line repressed the expression of BCL11B at both the protein and mRNA levels, whereas the transduction of HBZ had little effect on the expression. Tax mutants with a decreased activity for the NF-B, CREB or PDZ protein pathways still showed a reduced expression of the BCL11B protein, thereby implicating a different function of Tax in BCL11B downregulation. In addition, the HTLV-2 Tax2 protein reduced the BCL11B protein expression in T-cells. Seven HTLV-1-infected T-cell lines, including three ATL-derived cell lines, showed reduced BCL11B mRNA and protein expression relative to an uninfected T-cell line, and the greatest reductions were in the cells expressing Tax. Collectively, these results indicate that Tax is responsible for suppressing BCL11B protein expression in HTLV-1-infected T-cells; Tax-mediated repression of BCL11B is another mechanism that Tax uses to promote oncogenesis of HTLV-1-infected T-cells.
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| 9.
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Pinto, Mariana Tomazini ; Malta, Tathiane Maistro ; Rodrigues, Evandra Strazza ; Takayanagui, Osvaldo Massaiti ; Tanaka, Yuetsu ; Covas, Dimas Tadeu ; Kashima, Simone
概要:
Human T-lymphotropic virus type 1 (HTLV-1) is a human retrovirus related to the chronic neuroinflammatory disease HTLV-1
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-associated myelopathy/tropical spastic paraparesis (HAM/TSP). CD4^+ T cells activation appears to play a key role on HTLV-1 infection. Here we investigated the expression of genes associated to T cell activation CD3e molecule, epsilon (CD3ɛ), lymphocyte-specific protein tyrosine kinase (LCK), vav 1 guanine nucleotide exchange factor (VAV1), and zeta-chain (TCR) associated protein kinase 70 kDa (ZAP70) on T lymphocytes of HTLV-1-infected individuals and compared to healthy uninfected individuals (CT). We observed that CD3ɛ, LCK, ZAP70, and VAV1 gene expression were increased in CD4^+ T cells from HAM/TSP group compared to HTLV-1 asymptomatic patients (HAC). Moreover, ZAP70 and VAV1 were also upregulated in HAM/TSP compared to CT group. We detected a positive correlation among all these genes. We also observed that CD3ɛ, LCK, and VAV1 genes had a positive correlation with the proviral load (PVL) and Tax expression. These results suggest that PVL and Tax protein could drive CD3ɛ, LCK, and VAV1 gene expression in CD4^+ T cells, and these genes function on a synchronized way on the CD4^+ T cell activation. The elucidation of the mechanisms underlying T cell receptor signaling pathway is of considerable interest and might lead to new insights into the mechanism of HAM/TSP.
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