Functional impairment of Tax-specific but not cytomegalovirus-specific CD8+ T lymphocytes in a minor population of asymptomatic human T-cell leukemia virus type 1-carriers

Takamori, Ayako; Hasegawa, Atsuhiko; Utsunomiya, Atae; Maeda, Yasuhiro; Yamano, Yoshihisa; Masuda, Masato; Shimizu, Yukiko; Tamai, Yasukatsu; Sasada, Amane; Zeng, Na; Choi, Ilseung; Uike, Naokuni; Okamura, Jun; Watanabe, Toshiki; Masuda, Tohru; Kannagi, Mari

doi:10.1186/1742-4690-8-100

Cited by 30 publications

(40 citation statements)

References 54 publications

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“…The identification of these epitopes allowed us to monitor HTLV-1-specific CTLs and analyze their functions ex vivo by using antigen/HLA tetrameric complexes. In our study using Tax-specific tetramers on HLA-A2, -A11, or -A24-positive individuals, we detected Tax-specific CTLs in 100% of HAM/TSP patients, 87% of ACs, and 38% of chronic ATL (cATL) patients tested ( Figure 2 ; Takamori et al, 2011). …”

Section: Different Htlv-1-specific T-cell Responses Between Diseasesmentioning

confidence: 73%

The roles of acquired and innate immunity in human T-cell leukemia virus type 1-mediated diseases

Kannagi¹,

Hasegawa²,

Takamori³

et al. 2012

Front. Microbio.

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Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis in small subsets of HTLV-1 carriers. HTLV-1-specific T-cell responses play critical roles in anti-viral and anti-tumor host defense during HTLV-1 infections. Some HTLV-1 carriers exhibit selective loss or anergy of HTLV-1-specific T-cells at an asymptomatic stage. This is also observed in ATL patients and may therefore be an underlying risk factor of ATL in combination with elevated proviral loads. HTLV-1-specific T-cells often recognize the viral oncoprotein Tax, indicating expression of Tax protein in vivo, although levels of HTLV-1 gene expression are known to be very low. A type-I interferon (IFN) response can be induced by HTLV-1-infected cells and suppresses HTLV-1 expression in vitro, suggesting a role of type-I IFN response in viral suppression and pathogenesis in vivo. Both acquired and innate immune responses control the status of HTLV-1-infected cells and could be the important determinants in the development of HTLV-1-mediated malignant and inflammatory diseases.

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Section: Different Htlv-1-specific T-cell Responses Between Diseasesmentioning

confidence: 73%

The roles of acquired and innate immunity in human T-cell leukemia virus type 1-mediated diseases

Kannagi¹,

Hasegawa²,

Takamori³

et al. 2012

Front. Microbio.

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“…Mixed lymphocyte-peptide cultures were performed to stimulate Tax-specific CTLs, as described previously. 30 Briefly, splenocytes from HTLV-1-infected mice were cultured for 13 days with 10 mg/mL Tax301-309 peptide and 50 U/mL recombinant human IL-2 (Takeda Chemical Industries). Cultured splenocytes were then analyzed by flow cytometry.…”

Section: Flow Cytometric Analysis and Cell Sortingmentioning

confidence: 99%

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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“…During the development of ATL, general immune suppression has been reportedly due to dysfunction of Tax-specific CTLs [7, 20]. In addition, both IFN-γ production and proliferative capacity of tetramer-binding Tax-specific CD8 + T-cells are severely impaired in ATL patients [21], and a Tax-low or Tax-negative phenotype is associated with clonal proliferation of ATL cells [22, 23]. Consequently, it has been established that impairment of the Tax-specific response is critically involved in ATL induction and disease progression.…”

Section: Introductionmentioning

confidence: 99%

In vivo immunogenicity of Tax(11–19) epitope in HLA-A2/DTR transgenic mice: Implication for dendritic cell-based anti-HTLV-1 vaccine

Sagar

Masih

Schell

et al. 2014

Vaccine

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Viral oncoprotein Tax plays key roles in transformation of human T-cell leukemia virus (HTLV-1)-infected T cells leading to adult T-cell leukemia (ATL), and is the key antigen recognized during HTLV-associated myelopathy (HAM). In HLA-A2+ asymptomatic carriers as well as ATL and HAM patients, Tax(11-19) epitope exhibits immunodominance. Here, we evaluate CD8 T-cell immune response against this epitope in the presence and absence of dendritic cells (DCs) given the recent encouraging observations made with Phase 1 DC-based vaccine trial for ATL. To facilitate these studies, we first generated an HLA-A2/DTR hybrid mouse strain carrying the HLA-A2.1 and CD11c-DTR genes. We then studied CD8 T-cell immune response against Tax(11-19) epitope delivered in the absence or presence of Freund’s adjuvant and/or DCs. Overall results demonstrate that naturally presented Tax epitope could initiate an antigen-specific CD8 T cell response in vivo but failed to do so upon DC depletion. Presence of adjuvant potentiated Tax(11-19)-specific response. Elevated serum IL-6 levels coincided with depletion of DCs whereas decreased TGF-β was associated with adjuvant use. Thus, Tax(11-19) epitope is a potential candidate for the DC-based anti-HTLV-1 vaccine and the newly hybrid mouse strain could be used for investigating DC involvement in human class-I-restricted immune responses.

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Functional impairment of Tax-specific but not cytomegalovirus-specific CD8+ T lymphocytes in a minor population of asymptomatic human T-cell leukemia virus type 1-carriers

Cited by 30 publications

References 54 publications

The roles of acquired and innate immunity in human T-cell leukemia virus type 1-mediated diseases

The roles of acquired and innate immunity in human T-cell leukemia virus type 1-mediated diseases

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

In vivo immunogenicity of Tax(11–19) epitope in HLA-A2/DTR transgenic mice: Implication for dendritic cell-based anti-HTLV-1 vaccine

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