Advantage of higher-avidity CTL specific for Tax against human T-lymphotropic virus-1 infected cells and tumors

Kitazono, Takako; Okazaki, Taro; Araya, Natsumi; Yamano, Yoshihisa; Yamada, Yasuaki; Nakamura, Tatsufumi; Tanaka, Yuetsu; Ozaki, Shoichi

doi:10.1016/j.cellimm.2011.10.002

Cited by 7 publications

(6 citation statements)

References 44 publications

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“…More recent studies demonstrated a reduction in the strength of the immunological synapse in the presence of p8 [15]. This is in line with the finding that not only the number of HTLV-1-specific CTLs is important, but also their functional avidity [37] and even if they are abundant [38]–[40], they do not clear infection. Collectively our results suggest a model whereby a combination of effects of p8 and p12 on monocyte infectivity, viral transmission, and escape from CTL favors viral persistence (Figure 6).…”

Section: Discussionsupporting

confidence: 75%

Co-dependence of HTLV-1 p12 and p8 Functions in Virus Persistence

et al. 2014

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HTLV-1 orf-I is linked to immune evasion, viral replication and persistence. Examining the orf-I sequence of 160 HTLV-1-infected individuals; we found polymorphism of orf-I that alters the relative amounts of p12 and its cleavage product p8. Three groups were identified on the basis of p12 and p8 expression: predominantly p12, predominantly p8 and balanced expression of p12 and p8. We found a significant association between balanced expression of p12 and p8 with high viral DNA loads, a correlate of disease development. To determine the individual roles of p12 and p8 in viral persistence, we constructed infectious molecular clones expressing p12 and p8 (D26), predominantly p12 (G29S) or predominantly p8 (N26). As we previously showed, cells expressing N26 had a higher level of virus transmission in vitro. However, when inoculated into Rhesus macaques, cells producing N26 virus caused only a partial seroconversion in 3 of 4 animals and only 1 of those animals was HTLV-1 DNA positive by PCR. None of the animals exposed to G29S virus seroconverted or had detectable viral DNA. In contrast, 3 of 4 animals exposed to D26 virus seroconverted and were HTLV-1 positive by PCR. In vitro studies in THP-1 cells suggested that expression of p8 was sufficient for productive infection of monocytes. Since orf-I plays a role in T-cell activation and recognition; we compared the CTL response elicited by CD4+ T-cells infected with the different HTLV-1 clones. Although supernatant p19 levels and viral DNA loads for all four infected lines were similar, a significant difference in Tax-specific HLA.A2-restricted killing was observed. Cells infected with Orf-I-knockout virus (12KO), G29S or N26 were killed by CTLs, whereas cells infected with D26 virus were resistant to CTL killing. These results indicate that efficient viral persistence and spread require the combined functions of p12 and p8.

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Section: Discussionsupporting

confidence: 75%

Co-dependence of HTLV-1 p12 and p8 Functions in Virus Persistence

et al. 2014

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“…Therefore, we next examined whether antigen-specific T cell activation could induce ET-1 production from monocytes in mice. The tax-specific CTL line we developed recognizes a specific antigen, Tax11-19 peptide of HTLV-1 restricted with HLA-A2, upon activation in HLA-A2 transgenic HHD mice 25 , 26 . Tax-specific CTLs and mitomicyn C-treated syngeneic spleen cells from HHD mice were used as antigen-specific T cells and antigen-presenting cells, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…A tax-specific cytotoxic T lymphocyte (CTL) line was developed from HHD mice. Antigen-specific CTLs recognize the specific antigen of the Tax11-19 peptide of HTLV-1, LLFGYPVYV 25 .…”

Section: Methodsmentioning

confidence: 99%

T cells upon activation promote endothelin 1 production in monocytes via IFN-γ and TNF-α

Shinagawa

Okazaki

Ikeda

et al. 2017

Sci Rep

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Endothelin 1 (ET-1), mainly produced from vascular endothelial cells, induces vasoconstriction in physiological conditions. The endothelin receptor antagonist is among the most effective agents for pulmonary hypertension. However, little is known about the production source of ET-1 in inflammation and immunity. Here, we studied whether T cell-mediated ET-1 production system exists and operates independent of the production system in vascular endothelial cells. ET-1 production was readily detectable in the culture supernatant of human PBMCs and murine spleen cells stimulated with anti-CD3 antibody. Immunocytostaining showed that ET-1-producing cells emerged only in PBMCs stimulated with anti-CD3 antibody. Using the Transwell system, both murine and human monocytes sorted with magnetic beads in the inner chamber produced ET-1 when T cells were activated with antigen or anti-CD3 antibody in the outer chamber. This ET-1 production was inhibited by anti-IFN-γ and/or TNF-α antibody. Furthermore, monocytes purified from ETflox/flox;Tie2-Cre( + ) mice, which conditionally lack ET-1 in hematopoietic stem cells and vascular endothelial cells, did not produce ET-1 even when stimulated by antigen-specific T cell activation. This study demonstrates the existence of an immune-mediated ET-1 production induced by T cells upon activation through IFN-γ and TNF-α.

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“…These cells were also able to recognize a latent Tax level (detectable only by RT-PCR) produced by adult T-cell leukemia cells (ATLs), thus possibly leading to the prevention of HTLV-1 infection [122]. …”

Section: The Functional Avidity Of T Cells As a Correlate Of Immunmentioning

confidence: 99%

Functional Avidity: A Measure to Predict the Efficacy of Effector T Cells?

Viganó

Utzschneider

Perreau

et al. 2012

Clinical and Developmental Immunology

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The functional avidity is determined by exposing T-cell populations in vitro to different amounts of cognate antigen. T-cells with high functional avidity respond to low antigen doses. This in vitro measure is thought to correlate well with the in vivo effector capacity of T-cells. We here present the multifaceted factors determining and influencing the functional avidity of T-cells. We outline how changes in the functional avidity can occur over the course of an infection. This process, known as avidity maturation, can occur despite the fact that T-cells express a fixed TCR. Furthermore, examples are provided illustrating the importance of generating T-cell populations that exhibit a high functional avidity when responding to an infection or tumors. Furthermore, we discuss whether criteria based on which we evaluate an effective T-cell response to acute infections can also be applied to chronic infections such as HIV. Finally, we also focus on observations that high-avidity T-cells show higher signs of exhaustion and facilitate the emergence of virus escape variants. The review summarizes our current understanding of how this may occur as well as how T-cells of different functional avidity contribute to antiviral and anti-tumor immunity. Enhancing our knowledge in this field is relevant for tumor immunotherapy and vaccines design.

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Advantage of higher-avidity CTL specific for Tax against human T-lymphotropic virus-1 infected cells and tumors

Cited by 7 publications

References 44 publications

Co-dependence of HTLV-1 p12 and p8 Functions in Virus Persistence

Co-dependence of HTLV-1 p12 and p8 Functions in Virus Persistence

T cells upon activation promote endothelin 1 production in monocytes via IFN-γ and TNF-α

Functional Avidity: A Measure to Predict the Efficacy of Effector T Cells?

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