Adult T cell leukemia (ATL) is an aggressive hematologic disease caused by human T cell leukemia virus type 1 (HTLV-1) infection. Various animal models of HTLV-1 infection/ATL have been established to elucidate the pathogenesis of ATL and develop appropriate treatments. For analyses employing murine models, transgenic and immunodeficient mice are used because of the low infectivity of HTLV-1 in mice. Each mouse model has different characteristics that must be considered before use for different HTLV-1 research purposes. HTLV-1 Tax and HBZ transgenic mice spontaneously develop tumors, and the roles of both Tax and HBZ in cell transformation and tumor growth have been established. Severely immunodeficient mice were able to be engrafted with ATL cell lines and have been used in preclinical studies of candidate molecules for the treatment of ATL. HTLV-1-infected humanized mice with an established human immune system are a suitable model to characterize cells in the early stages of HTLV-1 infection. This review outlines the characteristics of mouse models of HTLV-1 infection/ATL and describes progress made in elucidating the pathogenesis of ATL and developing related therapies using these mice.

Adult T-cell leukemia (ATL) is an aggressive hematologic disease caused by human T-cell leukemia virus type 1 (HTLV-1) infection. Various animal models of HTLV-1 infection/ATL have been established to elucidate the pathogenesis of ATL and develop appropriate treatments. For analyses employing murine models, transgenic and immunodeficient mice are used because of the low infectivity of HTLV-1 in mice. HTLV-1 Tax and HBZ transgenic mice spontaneously develop tumors, and roles for both Tax and HBZ in cell transformation and tumor growth have been established. Severely immunodeficient mice were able to engraft ATL cell lines and have been used in preclinical studies of candidate molecules for the treatment of ATL. HTLV-1-infected humanized mice with an established human immune system are a suitable model to characterize cells in the early stages of HTLV-1 infection. This review outlines the characteristics of mouse models of HTLV-1 infection/ATL and describes progress made in elucidating the pathogenesis of ATL and developing related therapies using these mice.

Immune responses in humanized mice are generally inefficient without co-transplantation of human thymus or HLA transgenes. Previously, we generated humanized mice via the intra-bone marrow injection of CD133+ cord blood cells into irradiated adult immunodeficient mice (IBMI-huNSG mice), which could mount functional immune responses against HTLV-1, although the underlying mechanisms were still unknown. Here, we investigated thymocyte development in IBMI-huNSG mice, focusing on the roles of human and mouse MHC restriction. IBMI-huNSG mice had normal developmental profiles but aberrant thymic structures. Surprisingly, the thymic medulla-like regions expanded after immunization due to enhanced thymocyte expansion in association with the increase in HLA-DR+ cells, including CD205⁺ dendritic cells (DCs). The organ culture of thymus from immunized IBMI-huNSG mice with a neutralizing antibody to HLA-DR showed the HLA-DR-dependent expansion of CD4 single positive thymocytes. Mature peripheral T-cells exhibited alloreactive proliferation when co-cultured with human peripheral blood mononuclear cells. Live imaging of the thymus from immunized IBMI-huNSG mice revealed dynamic adhesive contacts of human-derived thymocytes and DCs accompanied by Rap1 activation. These findings demonstrate that an increase in HLA-DR+ cells by immunization promotes HLA-restricted thymocyte expansion in humanized mice, offering a unique opportunity to generate humanized mice with ease.

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory disease driven by HTLV-1-infected CD4⁺ T cells; however, the phenotypic and functional characteristics of disease-associated T-cell subsets remain incompletely understood. We analyzed samples using flow cytometry (n = 3–5 per group) and RNA-seq (n = 13), focusing on CADM1^highCD4⁺ T cells enriched for HTLV-1-infected cells to evaluate a transferrin receptor (TfR)-expressing subset. TfR⁺CADM1^highCD4⁺ T cells were detected in both asymptomatic carriers and patients with HAM, but their frequency among CD4⁺ T cells was higher in HAM patients. These cells exhibited a Treg-like phenotype with higher Foxp3 and CTLA-4 expression than TfR⁻ cells and showed increased Ki-67 positivity, consistent with proliferation. Despite this phenotype, they produced interferon-γ, indicating inflammatory potential, while Foxp3 expression was lower in HAM patients than in asymptomatic carriers, suggesting a more inflammatory phenotype. Furthermore, TfR transcript levels (RNA-seq TPM) correlated with clinical indicators of disease activity, including neopterin and CXCL10 protein levels, and the Osame motor disability score. Collectively, these findings suggest that TfR identifies a proliferative, Foxp3-low, Treg-like inflammatory CD4⁺ T-cell subset that is associated with disease activity in HAM.

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.