Protective effect of cytotoxic T lymphocytes targeting HTLV-1 bZIP factor

Sugata, Kenji; Yasunaga, Jun-ichirou; Mitobe, Yuichi; Miura, Michi; Miyazato, Paola; Kohara, Michinori; Matsuoka, Masao

doi:10.1182/blood-2015-04-641118

Cited by 59 publications

(75 citation statements)

References 49 publications

(57 reference statements)

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“…ATL clones have the potential to present a range of non-self antigens to CTL: for example, the consistently expressed HTLV-1 antigen HBZ[49], or neoepitopes generated by the frequent somatic mutations observed in ATL: a recent study detected 6404 somatic mutations in 81 ATL cases by exome sequencing [17]. Apart from the frequent loss of expression of the dominant CTL target antigen Tax by ATL clones, there was no evidence that these clones evaded the immune response by downregulation of MHC class 1; nevertheless, the bulk of ATL cells escaped CTL lysis in most individuals.…”

Section: Discussionmentioning

confidence: 99%

T Cell Receptor Vβ Staining Identifies the Malignant Clone in Adult T cell Leukemia and Reveals Killing of Leukemia Cells by Autologous CD8+ T cells

et al. 2016

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There is growing evidence that CD8+ cytotoxic T lymphocyte (CTL) responses can contribute to long-term remission of many malignancies. The etiological agent of adult T-cell leukemia/lymphoma (ATL), human T lymphotropic virus type-1 (HTLV-1), contains highly immunogenic CTL epitopes, but ATL patients typically have low frequencies of cytokine-producing HTLV-1-specific CD8+ cells in the circulation. It remains unclear whether patients with ATL possess CTLs that can kill the malignant HTLV-1 infected clone. Here we used flow cytometric staining of TCRVβ and cell adhesion molecule-1 (CADM1) to identify monoclonal populations of HTLV-1-infected T cells in the peripheral blood of patients with ATL. Thus, we quantified the rate of CD8+-mediated killing of the putative malignant clone in ex vivo blood samples. We observed that CD8+ cells from ATL patients were unable to lyse autologous ATL clones when tested directly ex vivo. However, short in vitro culture restored the ability of CD8+ cells to kill ex vivo ATL clones in some donors. The capacity of CD8+ cells to lyse HTLV-1 infected cells which expressed the viral sense strand gene products was significantly enhanced after in vitro culture, and donors with an ATL clone that expressed the HTLV-1 Tax gene were most likely to make a detectable lytic CD8+ response to the ATL cells. We conclude that some patients with ATL possess functional tumour-specific CTLs which could be exploited to contribute to control of the disease.

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Section: Discussionmentioning

confidence: 99%

T Cell Receptor Vβ Staining Identifies the Malignant Clone in Adult T cell Leukemia and Reveals Killing of Leukemia Cells by Autologous CD8+ T cells

et al. 2016

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“…We have also identified six distinct Tax regions that are targeted by STLV-1-specific CD8 ϩ T cells. While other HTLV-1 antigens, like HBZ, could be used as a vaccine target, their immunogenicity is usually weak and requires several boosts (25). Furthermore, Suemori and colleagues demonstrated that HBZ-specific CD8 ϩ T cells are scarcely detectable in HTLV-1 infections using HLA-A*0201/HBZ 26 -34 tetramer analysis (70).…”

Section: Cd8 ؉ T Cells From Several Stlv-1-infected Baboons Target Tamentioning

confidence: 99%

“…Moreover, while Tax transcripts can be detected in only 40% of ATL patients, HBZ is expressed in all ATL patients (23,24). In fact, Sugata and colleagues generated anti-HBZ-specific CD8 ϩ T cells in vivo in mice as well as in rhesus macaques, using recombinant vaccinia viruses (25). Although this approach is promising, HBZ immunogenicity was poor compared to that of Tax and required multiple boosts.…”

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confidence: 99%

Cellular Immune Responses against Simian T-Lymphotropic Virus Type 1 Target Tax in Infected Baboons

Castro

Giret

Magnani

et al. 2016

J Virol

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“…In this study, we used ATL cells (named Ht48) isolated from an HBZ-Tg mouse [27, 28]. To assess the tumor initiating and regeneration abilities of Ht48 cells in vivo , we transplanted 1×10 7 Ht48 cells into the C57BL/6-Ly5.1 mouse (Ly5.1) strain whose cells can be distinguished from the donor cells by FACS (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

Impact of the SCF signaling pathway on leukemia stem cell-mediated ATL initiation and progression in an HBZ transgenic mouse model

et al. 2016

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Adult T-cell leukemia (ATL) is a malignant disease caused by human T-lymphotropic virus type 1. In aggressive ATL, the response to chemotherapy is extremely poor. We hypothesized that this poor response is due to the existence of chemotherapy-resistant cells, such as leukemic stem cells. Previously, we successfully identified an ATL stem cell (ATLSC) candidate as the c-kit+/CD38−/CD71− cells in an ATL mouse model using Tax transgenic mice. Here, with a new ATL mouse model using HBZ-transgenic mice, we further discovered that the functional ATLSC candidate, which commonly expresses c-kit, is drug-resistant and has the ability to initiate tumors and reconstitute lymphomatous cells. We characterized the ATLSCs as c-kit+/CD4−/CD8− cells and found that they have a similar gene expression profile as T cell progenitors. Additionally, we found that AP-1 gene family members, including Junb, Jund, and Fosb, were up-regulated in the ATLSC fraction. The results of an in vitro assay showed that ATLSCs cultured with cytokines known to promote stem cell expansion, such as stem cell factor (SCF), showed highly proliferative activity and maintained their stem cell fraction. Inhibition of c-kit–SCF signaling with the neutralizing antibody ACK2 affected ATLSC self-renewal and proliferation. Experiments in Sl/Sld mice, which have a mutation in the membrane-bound c-kit ligand, found that ATL development was completely blocked in these mice. These results clearly suggest that the c-kit–SCF signal plays a key role in ATLSC self-renewal and in ATL initiation and disease progression.

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Protective effect of cytotoxic T lymphocytes targeting HTLV-1 bZIP factor

Abstract: Key Points• Vaccination with HBZ can induce cytotoxic T lymphocytes and suppress an HBZ-expressing lymphoma cell line in vivo.• Immunodominant epitopes of HBZ have been identified in mice, monkeys, and humans.

Cited by 59 publications

References 49 publications

T Cell Receptor Vβ Staining Identifies the Malignant Clone in Adult T cell Leukemia and Reveals Killing of Leukemia Cells by Autologous CD8+ T cells

T Cell Receptor Vβ Staining Identifies the Malignant Clone in Adult T cell Leukemia and Reveals Killing of Leukemia Cells by Autologous CD8+ T cells

Cellular Immune Responses against Simian T-Lymphotropic Virus Type 1 Target Tax in Infected Baboons

Impact of the SCF signaling pathway on leukemia stem cell-mediated ATL initiation and progression in an HBZ transgenic mouse model

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