Potential immunogenicity of adult T cell leukemia cells <i>in vivo</i>

Kurihara, Ken; Harashima, Nanae; Hanabuchi, Shino; Masuda, Masato; Utsunomiya, Atae; Tanosaki, Ryuji; Tomonaga, Masao; Ohashi, Takashi; Hasegawa, Atsuhiko; Masuda, Tohru; Okamura, Jun; Tanaka, Yuetsu; Kannagi, Mari

doi:10.1002/ijc.20737

Cited by 44 publications

(42 citation statements)

References 46 publications

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“…Our observations were qualitatively identical in donors who were asymptomatic, and those with inflammatory conditions. Our findings are also in agreement with those of Kurihara et al who showed that cultured PBMC from two patients with Adult T cell Leukaemia/Lymphoma (ATL) stimulated stronger responses than PBMCs from uninfected donors in a mixed lymphocyte reaction [38]. These changes in cellular phenotype were only observed after in vitro culture, and were not detected in fresh peripheral blood samples.…”

Section: Discussionsupporting

confidence: 93%

Cytotoxic T lymphocyte lysis of HTLV-1 infected cells is limited by weak HBZ protein expression, but non-specifically enhanced on induction of Tax expression

Rowan¹,

Suemori²,

Fujiwara³

et al. 2014

Retrovirology

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Background: Immunogenetic evidence indicates that cytotoxic T lymphocytes (CTLs) specific for the weak CTL antigen HBZ limit HTLV-1 proviral load in vivo, whereas there is no clear relationship between the proviral load and the frequency of CTLs specific for the immunodominant antigen Tax. In vivo, circulating HTLV-1-infected cells express HBZ mRNA in contrast, Tax expression is typically low or undetectable. To elucidate the virus-suppressing potential of CTLs targeting HBZ, we compared the ability of HBZ-and Tax-specific CTLs to lyse naturally-infected cells, by co-incubating HBZ-and Tax-specific CTL clones with primary CD4 + T cells from HLA-matched HTLV-1-infected donors. We quantified lysis of infected cells, and tested whether specific virus-induced host cell surface molecules determine the susceptibility of infected cells to CTL-mediated lysis.

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Section: Discussionsupporting

confidence: 93%

Cytotoxic T lymphocyte lysis of HTLV-1 infected cells is limited by weak HBZ protein expression, but non-specifically enhanced on induction of Tax expression

Rowan¹,

Suemori²,

Fujiwara³

et al. 2014

Retrovirology

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“…[42][43][44] To investigate whether Tax-specific CTLs were induced in HTLV-1-infected mice, the IBMI-huNOG mice were generated using hematopoietic stem cells purified from the cord blood of an HLA-A*24:02 haplotype individual. HLA-A*24:02 tetramers coupled with Tax301-309 were used to detect CTLs.…”

Section: Induction Of Htlv-1-specific Adaptive Immune Responses In Htmentioning

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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“…Consequently, a large number of MHC class I -restricted CTL epitopes derived from the Tax protein have been identified (6,13,14,20). However, we believe that the CD4 + helper T lymphocytes (HTL) also play an important role in HTLV-1 infection because HTLs are required for clonal expansion of antibodysecreting B cells and induction and maintenance of optimal CTL responses (21,22). Moreover, in some instances, HTLs can exhibit an effector function by directly recognizing and killing MHC class II + virus-infected or tumor cells that present peptide epitopes on their surface (23 -26).…”

mentioning

confidence: 99%

In vitroPeptide Immunization of Target Tax Protein Human T-Cell Leukemia Virus Type 1–Specific CD4+ Helper T Lymphocytes

Kobayashi

Ngato²,

Sato³

et al. 2006

Clinical Cancer Research

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Purpose: Adult T-cell leukemia/lymphoma induced by human T-cell leukemia virus type 1 (HTLV-1) is usually a fatal lymphoproliferative malignant disease. HTLV-1 Tax protein plays a critical role in HTLV-1-associated leukemogenesis and is an attractive target for vaccine development. Although HTLV-1Tax is the most dominant antigen for HTLV-1-specific CD8 + CTLs in HTLV-1-infected individuals, few epitopes recognized by CD4 + helper T lymphocytes in HTLV-1Tax protein have been described. The aim of the present study was to study T-helper-cell responses to HTLV-1 Tax and to identify naturally processed MHC class II^restricted epitopes that could be used for vaccine development. Experimental Design: An MHC class II binding peptide algorithm was used to predict potential T-helper cell epitope peptides from HTLV-1 Tax. We assessed the ability of the corresponding peptides to elicit helper T-cell responses by in vitro vaccination of purified CD4 + T lymphocytes. Results: Peptides Tax 191-205 and Tax 305-319 were effective in inducing T-helper-cell responses. Although Tax [191][192][193][194][195][196][197][198][199][200][201][202][203][204][205] was restricted by the HLA-DR1 and DR9 alleles, responses to Tax [305][306][307][308][309][310][311][312][313][314][315][316][317][318][319] were restricted by either DR15 or DQ9. Both these epitopes were found to be naturally processed by HTLV-1 + T-cell lymphoma cells and by autologous antigen-presenting cells that were pulsed with HTLV-1Tax + tumor lysates. Notably, the two newly identified helper T-cell epitopes are found to lie proximal to known CTL epitopes, which will facilitate the development of prophylactic peptide^based vaccine capable of inducing simultaneous CTL and T-helper responses. Conclusion: Our data suggest that HTLV-1 Tax protein could serve as tumor-associated antigen for CD4 + helper T cells and that the present epitopes might be used for T-cell-based immunotherapy against tumors expressing HTLV-1.

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Potential immunogenicity of adult T cell leukemia cells in vivo

Abstract: Experimental vaccines targeting human T cell leukemia virus type-I (HTLV-I

Cited by 44 publications

References 46 publications

Cytotoxic T lymphocyte lysis of HTLV-1 infected cells is limited by weak HBZ protein expression, but non-specifically enhanced on induction of Tax expression

Cytotoxic T lymphocyte lysis of HTLV-1 infected cells is limited by weak HBZ protein expression, but non-specifically enhanced on induction of Tax expression

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

In vitroPeptide Immunization of Target Tax Protein Human T-Cell Leukemia Virus Type 1–Specific CD4+ Helper T Lymphocytes

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