Abnormally High Levels of Virus-Infected IFN-γ+CCR4+CD4+CD25+ T Cells in a Retrovirus-Associated Neuroinflammatory Disorder

Yamano, Yoshihisa; Araya, Natsumi; Sato, Tomoo; Utsunomiya, Atae; Azakami, Kazuko; Hasegawa, Daisuke; Izumi, Toshihiko; Fujita, Hidetoshi; Aratani, Satoko; Yagishita, Naoko; Fujii, Ryoji; Nishioka, Kusuki; Jacobson, Steven; Nakajima, Takeshi

doi:10.1371/journal.pone.0006517

Cited by 104 publications

(128 citation statements)

References 45 publications

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“…Use of 1 μg/ml of either KM2760 or PSL was sufficient to suppress spontaneous proliferation of the PBMCs, as measured by 3 H-thymidine incorporation (P < 0.05 and P < 0.01, respectively; Figure 5D) as well as IFN-γ production (P < 0.05 and P < 0.001, respectively; Figure 5E). Similar results were observed in experiments using cells isolated from sion profile (19). We suspected that these infected cells may infiltrate the CNS and trigger an inflammatory positive feedback loop, ultimately leading to chronic spinal cord inflammation (27).…”

Section: Discussionsupporting

confidence: 81%

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HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells

Araya¹,

Sato²,

Ando³

et al. 2014

J. Clin. Invest.

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Section: Discussionsupporting

confidence: 81%

“…+ cells was higher in HAM/TSP versus ATLL patients despite similar proviral loads (19,20). Therefore, we hypothesized that HTLV-1 causes chronic inflammation by infecting …”

Section: Ccr4mentioning

confidence: 99%

HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells

Araya¹,

Sato²,

Ando³

et al. 2014

J. Clin. Invest.

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“…However, Tax expression was rapidly induced after short-term (16 h) cultivation ex vivo (Figure 2A, lower panel). Furthermore, these Tax-expressing CD4-positive cells were more frequently positive for chemokine (C-C motif ) receptor 4 (CCR4) than Tax-negative CD4-positive cells ( Figure 2B), as previously reported in natural HTLV-1 infections [17,18]. However, although most of the CD4- C. Genomic PCR to confirm HTLV-1 infection.…”

Section: Resultssupporting

confidence: 75%

The neutralizing function of the anti-HTLV-1 antibody is essential in preventing in vivo transmission of HTLV-1 to human T cells in NOD-SCID/¿cnull (NOG) mice

et al. 2014

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Background: Human T-cell leukemia virus type 1 (HTLV-1) causes both neoplastic and inflammatory diseases, including adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Because these life-threatening and disabling diseases are not yet curable, it is important to prevent new HTLV-1 infections.Findings: In this study, we have established a simple humanized mouse model of HTLV-1 infection for evaluating prophylactic and therapeutic interventions. In this model, HTLV-1-negative normal human peripheral blood mononuclear cells (PBMCs) are transplanted directly into the spleens of severely immunodeficient NOD-SCID/γcnull (NOG) mice, together with mitomycin-treated HTLV-1-producing T cells. Using this model, we tested the efficacy of monoclonal antibodies (mAbs) specific to HTLV-1 as well as human IgG isolated from HAM/TSP patients (HAM-IgG) in preventing HTLV-1-infection. One hour before and 24 h after transplantation of the human cells, each antibody sample was inoculated intraperitoneally. On day 14, human PBMCs isolated from the mouse spleens were tested for HTLV-1 infection. Whereas fresh CD4-positive and CD8-positive T cells isolated from untreated mice or mice treated with isotype control mAb, HTLV-1 non-neutralizing mAbs to envelope gp46, gag p19, and normal human IgG were all infected with HTLV-1; the mice treated with either HTLV-1 neutralizing anti-gp46 mAb or HAM-IgG did not become infected.Conclusions: Our data indicate that the neutralizing function of the antibody, but not the antigen specificity, is essential for preventing the in vivo transmission of HTLV-1. The present animal model will also be useful for the in vivo evaluation of the efficacy of candidate molecules to be used as prophylactic and therapeutic intervention against HTLV-1 infection.

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“…35 HTLV-1-infected humanized mice showed marked expansion of CD25 1 CD4 T cells in the spleen relative to mock-infected controls ( Figure 2D; Table 1), as is observed in peripheral blood of ATL and HAM/TSP patients. 9,36 Furthermore, PVLs in the spleen were significantly correlated with the rate of CD25 1 CD4 T cells ( Figure 2E). These data suggest that the expanded CD25 1 CD4 Tcell population represents the majority of HTLV-1-infected cells in vivo.…”

Section: Proliferation Of Htlv-1-infected T Cells In Ibmi-hunog Micementioning

confidence: 86%

An animal model of adult T-cell leukemia: humanized mice with HTLV-1–specific immunity

Tezuka

Xun

Tei

et al. 2014

Blood

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Key Points• Humanized mice, IBMIhuNOG, were generated by intra-bone marrow injection of human CD1331 hematopoietic stem cells.• HTLV-1-infected IBMIhuNOG mice recapitulated distinct ATL-like symptoms as well as HTLV-1-specific adaptive immune responses.Human T-cell leukemia virus type 1 (HTLV-1) is causally associated with adult T-cell leukemia (ATL), an aggressive T-cell malignancy with a poor prognosis. To elucidate ATL pathogenesis in vivo, a variety of animal models have been established; however, the mechanisms driving this disorder remain poorly understood due to deficiencies in each of these animal models. Here, we report a novel HTLV-1-infected humanized mouse model generated by intra-bone marrow injection of human CD133 1 stem cells into NOD/Shi-scid/IL-2Rgc null (NOG) mice (IBMI-huNOG mice).Upon infection, the number of CD4 1 human T cells in the periphery increased rapidly, and atypical lymphocytes with lobulated nuclei resembling ATL-specific flower cells were observed 4 to 5 months after infection. Proliferation was seen in both CD25 2 and CD25 1 CD4 T cells with identical proviral integration sites; however, a limited number of CD25 1 -infected T-cell clones eventually dominated, indicating an association between clonal selection of infected T cells and expression of CD25. Additionally, HTLV-1-specific adaptive immune responses were induced in infected mice and might be involved in the control of HTLV-1-infected cells. Thus, the HTLV-1-infected IBMI-huNOG mouse model successfully recapitulated the development of ATL and may serve as an important tool for investigating in vivo mechanisms of ATL leukemogenesis and evaluating anti-ATL drug and vaccine candidates. (Blood. 2014;123(3):346-355)

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Abnormally High Levels of Virus-Infected IFN-γ+CCR4+CD4+CD25+ T Cells in a Retrovirus-Associated Neuroinflammatory Disorder

Cited by 104 publications

References 45 publications

HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells

HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells

The neutralizing function of the anti-HTLV-1 antibody is essential in preventing in vivo transmission of HTLV-1 to human T cells in NOD-SCID/¿cnull (NOG) mice

An animal model of adult T-cell leukemia: humanized mice with HTLV-1–specific immunity

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