Search Results (66)

Beyond their traditional role as short-lived antimicrobial cells, neutrophils are increasingly recognized as key regulators of adaptive immunity and tumor progression. This AI-assisted integrative review investigated the neutrophil–T-cell axis, particularly the role of Galectin-9 (Gal-9), across adult T-cell leukemia/lymphoma (ATL), Sézary syndrome (SS), coronavirus disease 2019 (COVID-19), and psoriasis. Leveraging AI tools (GPT-5 and Adobe Acrobat AI Assistant) for literature synthesis (2000–2025) and expert validation, we aimed to identify common immunological mechanisms. Across all conditions, neutrophils displayed persistent activation, elevated Gal-9 expression, and modulated T-cell interactions. In ATL and SS, neutrophilia correlated with poor survival and TCR signaling dysregulation, suggesting Gal-9-mediated immune modulation. In COVID-19 and psoriasis, neutrophil-derived Gal-9-linked innate hyperactivation to T-cell exhaustion and IL-17-driven inflammation. These findings define a recurring neutrophil–Gal-9 regulatory module connecting innate and adaptive immune responses. This study underscores the feasibility of combining AI-driven literature synthesis with expert review to identify unifying immunological mechanisms and therapeutic targets across malignancy and inflammation. Full article

Clarifying the function of approximately 20,000 proteins encoded by the human genome is a key challenge in the fields of medicine and biology. However, many proteins remain uncharacterized. In this review, we introduce a challenge that uses adult T-cell leukemia/lymphoma (ATL) and proteomics to study human proteins of unknown function (PUFs). The characteristic properties of ATL cells are as follows: ATL cells (1) are infected with virus, (2) are derived from CD4⁺ T cells, (3) are generated via multi-stage carcinogenesis, (4) have flower-like nuclei, and (5) are highly infiltrative in the aggressive type. Given that ATL cells have contributed to impressive basic research, such as the discovery of HTLV-1 as a human cancer virus and interleukin-2 (IL-2) receptor α chain (IL-2Rα)/CD25, which is used for identifying regulatory T (Treg) cells, ATL cell lines could still be considered an attractive research tool. Furthermore, the “Unknome database” is useful for examining function-unknown degrees of proteins of interest using known scores based on Gene Ontology (GO) annotations and protein analysis through evolutionary relationships (PANTHER). Combining ATL proteomic data obtained by us with the “Unknome database” is expected to contribute not only to investigating the pathogenetic mechanism of ATL but also to clarifying the functions of PUFs. Full article

Since forkhead box P3 (FOXP3) is a hallmark of regulatory T (Treg) cells, the expansion of FOXP3⁺ adult T-cell leukemia/lymphoma (ATL) cells is believed to contribute to immune suppression and the pathogenesis of ATL. However, the mechanisms underlying the expansion of FOXP3⁺ ATL cells remain unclear. OX40, a co-stimulatory molecule, is expressed in ATL cells, and OX40 signaling has been shown to promote the differentiation and proliferation of Treg cells in mouse models. To investigate the mechanisms driving the expansion of FOXP3⁺ ATL cells, we examined the expression of OX40 and its ligand, OX40L. Our findings revealed that OX40 expression was elevated in patients with ATL and with a high frequency of FOXP3⁺ ATL cells. Flow cytometric analysis of peripheral blood mononuclear cells (PBMCs) from patients with acute ATL cultured for 18 h demonstrated that FOXP3⁻ and FOXP3⁺ cells predominantly expressed OX40L and OX40, respectively. Furthermore, small interfering RNA-mediated FOXP3 knockdown in HTLV-1-infected cell lines increased OX40L expression. These results suggest that interactions between FOXP3⁻ OX40L⁺ cells and FOXP3⁺ OX40⁺ cells may promote the proliferation of FOXP3⁺ ATL cells. Full article

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATL). The trans-activator protein Tax of HTLV-1 is thought to play a crucial role in the early-stage transformation of the virus-infected cells. Tax is a multi-functional protein and modulates cellular signaling pathways that promote proliferation and survival of HTLV-1-infected cells, primarily through the trans-activation of cellular target genes. Tax interacts with a variety of host cell factors including signal transducers and transcription factors, leading to the activation of transcription factors such as CREB, NF-κB, and SRF and activates both its own promoter and those of a variety of host cellular genes. Tax activates its own promoter mainly through CREB and host cellular genes through NF-κB, SRF, and CREB. Accumulating evidence indicates that the Tax-mediated trans-activation of target genes through NF-κB plays an essential role in the transformation of HTLV-1 infected cells. However, the repertoire of Tax target genes, especially those crucial for leukemogenesis, are not known in detail. In this review, we summarize transcriptional activation mechanisms and target genes of Tax, especially focusing on transformation, to facilitate understanding of the underlying mechanisms of leukemogenesis induced by HTLV-1 infection. Full article

Human T-cell leukemia virus type 1 (HTLV-1), the first identified human retrovirus, is associated with adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The lack of effective antiviral therapies or vaccines highlights the critical importance of early diagnosis in managing HTLV-1-associated diseases. However, current commercial immunoassays, including enzyme immunoassays, line immunoassays, particle agglutination tests, and Western blots, are often limited by the need for specialized equipment and high costs, which restrict their accessibility in resource-poor regions. To address these challenges, we developed a novel dot-blot immunoassay using HTLV-1 P19 and GP46 synthetic peptides in combination with a precipitating tetramethylbenzidine (TMB) substrate. This innovative approach enables instrument-free visual detection through the formation of distinct blue-brown precipitates. Validation of this immunoassay with 179 clinical serum samples demonstrated 100% specificity and 91% sensitivity. Our assay offers a simple, cost-effective, and field-applicable diagnostic solution for HTLV-1 screening in resource-limited settings, potentially enhancing global surveillance of this neglected pathogen. Full article

Human T-cell leukemia virus type 1 (HTLV-1) establishes lifelong infection and is associated with severe diseases such as adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Cytotoxic T lymphocytes (CTLs), especially those specific for the viral protein Tax, play a pivotal role in controlling HTLV-1 infection. However, conventional humanized mouse models fail to fully reconstitute human immune responses, limiting their utility for evaluating CTL-mediated immunity. This study aimed to establish a physiologically relevant in vivo model to investigate human CTL responses against HTLV-1. To achieve this, we utilized NOG-HLA-A02 transgenic (Tg) mice expressing human HLA-A02:01 on thymic epithelial cells, enabling proper development of HLA-restricted human T cells. Compared to conventional humanized NOG mice, HTLV-1-infected humanized NOG-HLA-A02 Tg mice exhibited significantly reduced HTLV-1 proviral load (PVL), decreased expansion of infected CD4⁺ T cells, a trend toward increased frequencies of Tax-specific CD8⁺ T cells, and prolonged survival. These results demonstrate that the expression of HLA-A02:01 facilitates robust CTL-mediated immune control of HTLV-1. This model provides a powerful platform for dissecting HTLV-1 immunopathogenesis and evaluating CTL-targeted therapeutic strategies, including vaccines and immune checkpoint inhibitors. Full article

Human T cell leukemia virus type 1 (HTLV 1) is an oncogenic retrovirus responsible for the development of adult T cell leukemia (ATL). The minus strand of HTLV-1 provirus encodes an oncoprotein named HTLV-1 bZIP factor (HBZ), which plays a pivotal role in viral replication and T cell proliferation. Of particular interest is the spliced HBZ isoform (sHBZ), which is predominantly expressed in ATL cells and localizes within the nucleolus, conferring immortalizing properties to T cells. Our previous study has shown that sHBZ colocalizes and associates with Nucleophosmin/B23, a nucleolar phosphoprotein with multiple functions. In this study, through an optimized nucleolar isolation method, we first confirmed sHBZ’s nucleolar localization via Western blotting in transfected HEK293T cells, chronically HTLV-1-infected T cell lines, and freshly infected HeLa cells. We further demonstrated that the sHBZ/B23 association predominantly occurs in the nucleolus by co-immunoprecipitation of cell fractions. Our study highlights the nucleolar localization of sHBZ and its possibly essential interaction with this nucleolar-residing protein, leading to cell immortalization. Full article

T-cell malignancies represent a group of complex cancers arising from T cells and include aggressive subtypes such as Adult T-cell Leukemia/Lymphoma (ATL) and T-cell Acute Lymphoblastic Leukemia (T-ALL). Patients with these aggressive subtypes still represent an unmet medical condition. The synthetic adamantyl retinoid ST1926, a potent DNA polymerase-α inhibitor, proved a promising potency in preclinical models of ATL and peripheral T-cell lymphoma. Using advanced liquid chromatography–mass spectrometry (LC–MS/MS) techniques, we explored the effects of ST1926 on global protein expression in ATL (HuT-102) and T-ALL (MOLT-4) cells. We demonstrate that ST1926 triggers differentiation and apoptosis in malignant T-cells while halting tumor progression. Evidence at the proteomics level reveals the impact of ST1926 on crucial DNA replication enzymes and cell cycle regulation, highlighting its potential to reduce leukemogenesis and promote apoptosis. Our findings underscore the potential of ST1926 as an innovative therapeutic approach to address these aggressive T-cell malignancies, providing valuable insights into developing new targeted therapies and improving the outcomes and prognosis of patients with these challenging diseases. Full article

Human T-lymphotropic viruses (HTLVs) are deltaretroviruses infecting millions of individuals worldwide, with HTLV-1 and HTLV-2 being the most widespread and clinically relevant types. HTLV-1 is associated with severe diseases such as adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), while HTLV-2 shows a lower pathogenic potential, with occasional links to neurological disorders. HTLV-3 and HTLV-4, identified in Central Africa, remain poorly characterized but are genetically close to their simian counterparts, indicating recent zoonotic transmission events. HTLVs replicate through a complex cycle involving cell-to-cell transmission and clonal expansion of infected lymphocytes. Viral persistence is mediated by regulatory and accessory proteins, notably Tax and HBZ in HTLV-1, which alter host cell signaling, immune responses, and genomic stability. Integration of proviral DNA into transcriptionally active regions of the host genome may contribute to oncogenesis and long-term viral latency. Differences in viral protein function and intracellular localization contribute to the distinct pathogenesis observed between HTLV-1 and HTLV-2. Geographically, HTLV-1 shows endemic clusters in southwestern Japan, sub-Saharan Africa, the Caribbean, South America, and parts of the Middle East and Oceania. HTLV-2 is concentrated among Indigenous populations in the Americas and people who inject drugs in Europe and North America. Transmission occurs primarily via breastfeeding, sexual contact, contaminated blood products, and, in some regions, zoonotic spillover. Diagnostic approaches include serological screening (ELISA, Western blot, LIA) and molecular assays (PCR, qPCR), with novel biosensor and AI-based methods under development. Despite advances in understanding viral biology, therapeutic options remain limited, and preventive strategies focus on transmission control. The long latency period, lack of effective treatments, and global neglect complicate public health responses, underscoring the need for increased awareness, research investment, and targeted interventions. Full article

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with adult T-cell leukemia (ATL), a hematological malignancy, and HTLV-1-associated myelopathy (HAM), a progressive neurological disorder. HTLV-1 predominantly infects CD4+ T cells in vivo. The T-cell receptor (TCR)/CD3 complex on CD4+ helper T cells plays a pivotal role in immune responses by recognizing antigens and facilitating coordination with other immune cells. Dysfunction of the TCR/CD3 complex may impair immune function. Although CD3 downregulation has been identified as a characteristic of ATL cells, it remains uncertain whether a similar downregulation occurs in HTLV-1-infected cells from HAM patients. We hypothesized that HTLV-1 infection leads to TCR and CD3 downregulation, contributing to immune dysfunction in HAM patients. To test this hypothesis, we analyzed TCR/CD3 expression, TCR signaling, and immune responses in HTLV-1-infected cells from HAM patients. Intracellular HTLV-1 Tax detection revealed that HTLV-1 preferentially targets CD4+ over CD8+ T cells. CD3 and TCR expression levels were significantly lower in CD4+ T cells from HAM patients compared to healthy controls. Furthermore, HTLV-1-infected cells exhibited markedly reduced CD3 and TCR expression compared to uninfected cells. Impairments in TCR signaling, assessed through Lck and ZAP70 phosphorylation upon CD3 stimulation, were observed in CD4+ T cells from HAM patients compared to those from healthy controls. Notably, this reduction in TCR signaling was more pronounced in HTLV-1-infected CD4+ T cells than in uninfected CD4+ T cells in HAM patients. Additionally, cytomegalovirus (CMV)-specific CD4+ T cells detected by an addition of CMV antigens demonstrated reduced interferon-γ production in HTLV-1-infected cells compared to their uninfected counterparts. These findings suggest that TCR/CD3 downregulation and impaired TCR signaling contribute to immune dysfunction in HTLV-1-infected CD4+ T cells. As CD4+ T cells play a central role in immune responses, this mechanism may partially explain the cellular immune dysfunction to other pathogens observed in HAM patients. Full article

Human T-cell leukemia virus (HTLV-1) is the etiological agent of lymphoproliferative diseases such as adult T-cell leukemia and T-cell lymphoma (ATL) and a neurodegenerative disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). While several molecular clones of HTLV-1 have been published, all were isolated from samples derived from patients with adult T-cell leukemia. Here, we report the characterization of an HTLV-1 infectious molecular clone isolated from a sample of a patient with HAM/TSP disease. Genetic comparative analyses of the HAM/TSP molecular clone (pBST) revealed unique genetic alterations and specific viral mRNA expression patterns. Interestingly, our clone also harbors characteristics previously published to favor the development of HAM/TSP disease. The molecular clone is capable of infection and immortalization of human primary T cells in vitro. Our studies further demonstrate that the HTLV-1 virus produced from primary T cells transfected with pBST or ACH molecular clones cannot sustain long-term expansion, and cells cease to proliferate after 3–4 months in culture. In contrast, long-term proliferation and immortalization were achieved if the virus was transmitted from dendritic cells to primary T cells, and secondary infection of 729B cells in vitro was demonstrated. In both primary T cells and 729B cells, pBST and ACH were latent, and only hbz viral RNA was detected. This study suggests that HTLV-1 transmission from DC to T cells favors the immortalization of latently infected cells. Full article

Background: Adult T-cell leukemia/lymphoma (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1) after a long latent infection. HTLV-1 induces the indolent or aggressive type of leukemia in 5% of HTLV-1 carriers. ATL, especially the aggressive type, is resistant to multi-agent chemotherapy. The indolent type often progresses to the aggressive type. Even in the most indolent-type cases, that is, smoldering ATL, the average survival time is 55.0 months. Case Presentation: Five patients with ATL were followed up for their clinical course after amplified natural killer cell (ANK) therapy. Four patients who received ANK therapy as first-line therapy achieved complete remission and showed long-term survival without aggressive conversion or relapse for more than 5 years. One patient was treated with multiagent chemotherapy due to acute exacerbation but relapsed 2 months later. She was subsequently treated with radiation and ANK therapy and survived for more than 6 years. Furthermore, ANK therapy enhanced the immune function of ATL patients to a level higher than that of normal individuals. Conclusions: ANK therapy has great potential as first-line treatment for ATL. Full article

Human T-cell leukemia virus type-1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL). The trans-activator protein Tax of HTLV-1 plays crucial roles in leukemogenesis by promoting proliferation of virus-infected cells through activation of growth-promoting genes. However, critical target genes are yet to be elucidated. We show here that Tax activates the gene coding for cyclin-dependent kinase 7 (CDK7), the essential component of both CDK-activating kinase (CAK) and general transcription factor TFIIH. CAK and TFIIH play essential roles in cell cycle progression and transcription by activating CDKs and facilitating transcriptional initiation, respectively. Tax induced CDK7 gene expression not only in human T-cell lines but also in normal peripheral blood lymphocytes (PHA-PBLs) along with increased protein expression. Tax stimulated phosphorylation of CDK2 and RNA polymerase II at sites reported to be mediated by CDK7. Tax activated the CDK7 promoter through the NF-κB pathway, which mainly mediates cell growth promotion by Tax. Knockdown of CDK7 expression reduced Tax-mediated induction of target gene expression and cell cycle progression. These results suggest that the CDK7 gene is a crucial target of Tax-mediated trans-activation to promote cell proliferation by activating CDKs and transcription. Full article

The Notch pathway is a key cancer driver and is important in tumor progression. Early research suggested that Notch activity was highly dependent on the expression of the intracellular cleaved domain of Notch-1 (NICD). However, recent insights into Notch signaling reveal the presence of Notch pathway signatures, which may vary depending on different cancer types and tumor microenvironments. Herein, we perform a comprehensive investigation of the Notch signaling pathway in adult T-cell leukemia (ATL) primary patient samples. Using gene arrays, we demonstrate that the Notch pathway is constitutively activated in ATL patient samples. Furthermore, the activation of Notch in ATL cells remains elevated irrespective of the presence of activating mutations in Notch itself or its repressor, FBXW7, and that ATL cells are dependent upon Notch-1 expression for proliferation and survival. We demonstrate that ATL cells exhibit the expression of pivotal Notch-related genes, including notch-1, hes1, c-myc, H19, and hes4, thereby defining a critical Notch signature associated with ATL disease. Finally, we demonstrate that lncRNA H19 is highly expressed in ATL patient samples and ATL cells and contributes to Notch signaling activation. Collectively, our results shed further light on the Notch pathway in ATL leukemia and reveal new therapeutic approaches to inhibit Notch activation in ATL cells. Full article

γδ T cells and natural killer (NK) cells have attracted much attention as promising effector cell subsets for adoptive transfer for use in the treatment of malignant and infectious diseases, because they exhibit potent cytotoxic activity against a variety of malignant tumors, as well as virus-infected cells, in a major histocompatibility complex (MHC)-unrestricted manner. In addition, γδ T cells and NK cells express a high level of CD16, a receptor required for antibody-dependent cellular cytotoxicity. Adult T-cell leukemia–lymphoma (ATL) is caused by human T-lymphotropic virus type I (HTLV-1) and is characterized by the proliferation of malignant peripheral CD4⁺ T cells. Although several treatments, such as chemotherapy, monoclonal antibodies, and allogeneic hematopoietic stem cell transplantation, are currently available, their efficacy is limited. In order to develop alternative therapeutic modalities, we considered the possibility of infusion therapy harnessing γδ T cells and NK cells expanded using a novel nitrogen-containing bisphosphonate prodrug (PTA) and interleukin (IL)-2/IL-18, and we examined the efficacy of the cell-based therapy for ATL in vitro. Peripheral blood samples were collected from 55 patients with ATL and peripheral blood mononuclear cells (PBMCs) were stimulated with PTA and IL-2/IL-18 for 11 days to expand γδ T cells and NK cells. To expand NK cells alone, CD3⁺ T-cell-depleted PBMCs were cultured with IL-2/IL-18 for 10 days. Subsequently, the expanded cells were examined for cytotoxicity against ATL cell lines in vitro. The proportion of γδ T cells in PBMCs was markedly low in elderly ATL patients. The median expansion rate of the γδ T cells was 1998-fold, and it was 12-fold for the NK cells, indicating that γδ T cells derived from ATL patients were efficiently expanded ex vivo, irrespective of aging and HTLV-1 infection status. Anti-CCR4 antibodies enhanced the cytotoxic activity of the γδ T cells and NK cells against HTLV-1-infected CCR4-expressing CD4⁺ T cells in an antibody concentration-dependent manner. Taken together, the adoptive transfer of γδ T cells and NK cells expanded with PTA/IL-2/IL-18 is a promising alternative therapy for ATL. Full article