Abundant Tax protein expression in CD4+ T cells infected with human T-cell lymphotropic virus type I (HTLV-I) is prevented by cytotoxic T lymphocytes

Blood ◽  
2000 ◽  
Vol 95 (4) ◽  
pp. 1386-1392 ◽  
Author(s):  
Emmanuel Hanon ◽  
Sarah Hall ◽  
Graham P. Taylor ◽  
Mineki Saito ◽  
Ricardo Davis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Type ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Type I ◽  
Ctl Response ◽  
Specific Ctls ◽  
Human T Cell

The role of the cellular immune response in human T-cell leukemia virus type I (HTLV-I) infection is not fully understood. A persistently activated cytotoxic T lymphocyte (CTL) response to HTLV-I is found in the majority of infected individuals. However, it remains unclear whether this CTL response is protective or causes tissue damage. In addition, several observations paradoxically suggest that HTLV-I is transcriptionally silent in most infected cells and, therefore, not detectable by virus-specific CTLs. With the use of a new flow cytometric procedure, we show here that a high proportion of naturally infected CD4+ peripheral blood mononuclear cells (PBMC) (between 10% and 80%) are capable of expressing Tax, the immunodominant target antigen recognized by virus-specific CTLs. Furthermore, we provide direct evidence that autologous CD8+ T cells rapidly kill CD4+ cells naturally infected with HTLV-I and expressing Tax in vitro by a perforin-dependent mechanism. Consistent with these observations, we observed a significant negative correlation between the frequency of Tax11-19-specific CD8+ T cells and the percentage of CD4+ T cells in peripheral blood of patients infected with HTLV-I. Those results are in accordance with the view that virus-specific CTLs participate in a highly efficient immune surveillance mechanism that persistently destroys Tax-expressing HTLV-I-infected CD4+ T cells in vivo.

CD8+ T cells are an in vivo reservoir for human T-cell lymphotropic virus type I

Blood ◽  
2001 ◽  
Vol 98 (6) ◽  
pp. 1858-1861 ◽  
Author(s):  
Masahiro Nagai ◽  
Meghan B. Brennan ◽  
Jill A. Sakai ◽  
Carlos A. Mora ◽  
Steven Jacobson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Type ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Spastic Paraparesis ◽  
Type I ◽  
Human T Cell

Abstract It is thought that human T-cell lymphotropic virus type I (HTLV-I) preferentially infects CD4+ T cells in vivo. However, observations of high HTLV-I proviral load in patients with HTLV-I–associated myelopathy/tropical spastic paraparesis suggest that HTLV-I may infect other cell types in addition to CD4+ T cells. To identify in vivo T-cell tropisms of HTLV-I, real-time quantitative polymerase chain reaction (PCR) and intracellular protein staining were used. A high amount of HTLV-I proviral DNA was detected from purified CD8+ T cells by quantitative PCR (between 1.64 and 62.83 copies of HTLV-I provirus per 100 isolated CD8+ T cells). CD8+ T cells expressed HTLV-I–related antigens (HTLV-I Tax and p19 protein) after a short time in cultivation. These results demonstrate that CD8+ T cells are also infected with HTLV-I and express HTLV-I antigens at levels that are comparable to HTLV-I–infected CD4+ cells. Therefore, CD8+ cells are an additional viral reservoir in vivo for HTLV-I and may contribute to the pathogenesis of HTLV-I–mediated disorders.

scholarly journals Human T Cell Lymphotropic Virus Type I (HTLV-I)-Specific CD4+T Cells: Immunodominance Hierarchy and Preferential Infection with HTLV-I

2004 ◽  
Vol 172 (3) ◽  
pp. 1735-1743 ◽  
Author(s):  
Peter K. C. Goon ◽  
Tadahiko Igakura ◽  
Emmanuel Hanon ◽  
Angelina J. Mosley ◽  
Anna Barfield ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Type ◽  
Cd4 T Cells ◽  
Type I ◽  
Human T Cell

scholarly journals Retrovirally induced CTL degranulation mediated by IL-15 expression and infection of mononuclear phagocytes in patients with HTLV-I–associated neurologic disease

Blood ◽  
2008 ◽  
Vol 112 (6) ◽  
pp. 2400-2410 ◽  
Author(s):  
Yoshimi Enose-Akahata ◽  
Unsong Oh ◽  
Christian Grant ◽  
Steven Jacobson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Spastic Paraparesis ◽  
Cd8 T Cell ◽  
Mononuclear Phagocytes ◽  
Type I ◽  
Human T Cell ◽  
Ifn Γ

AbstractCD8+ T cells contribute to central nervous system inflammation in human T-cell lymphotropic virus type I (HTLV-I)–associated myelopathy/tropical spastic paraparesis (HAM/TSP). We analyzed CD8+ T-cell dysfunction (degranulation and IFN-γ production) and have demonstrated that CD8+ T cells of patients with HAM/TSP (HAM/TSP patients) spontaneously degranulate and express IFN-γ in ex vivo unstimulated culture. CD8+ T cells of HTLV-I asymptomatic carriers and healthy donors did not. Spontaneous degranulation was detected in Tax11-19/HLA-A*201 tetramer+ cells, but not in CMV pp65 tetramer+ cells. Interestingly, degranulation and IFN-γ production in CD8+ T cells was induced by coculture with autologous CD14+ cells, but not CD4+ T cells, of HAM/TSP patients, which correlated with proviral DNA load in CD14+ cells of infected patients. Moreover, the expression of IL-15, which induced degranulation and IFN-γ production in infected patients, was enhanced on surface of CD14+ cells in HAM/TSP patients. Blockade of MHC class I and IL-15 confirmed these results. Thus, CD8+ T-cell dysregulation was mediated by both virus infection and enhanced IL-15 on CD14+ cells in HAM/TSP patients. Despite lower viral expression than in CD4+ T cells, HTLV-I–infected or –activated CD14+ cells may be a heretofore important but under recognized reservoir particularly in HAM/TSP patients.

In vitro spontaneous lymphoproliferation in patients with human T-cell lymphotropic virus type I–associated neurologic disease: predominant expansion of CD8+ T cells

Blood ◽  
2001 ◽  
Vol 98 (5) ◽  
pp. 1506-1511 ◽  
Author(s):  
Jill A. Sakai ◽  
Masahiro Nagai ◽  
Meghan B. Brennan ◽  
Carlos A. Mora ◽  
Steven Jacobson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Type ◽  
Cd8 T Cells ◽  
Proviral Load ◽  
Mononuclear Cells ◽  
Spastic Paraparesis ◽  
Type I ◽  
Human T Cell

Peripheral blood mononuclear cells (PBMCs) from patients with human T-cell lymphotropic virus type I (HTLV-I)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) proliferate spontaneously in vitro. This spontaneous lymphoproliferation (SP) is one of the immunologic hallmarks of HAM/TSP and is considered to be an important factor related to the pathogenesis of HAM/TSP. However, the cell populations involved in this phenomenon have not yet been definitively identified. To address this issue, the study directly evaluated proliferating cell subsets in SP with a flow cytometric method using bromodeoxyuridine and Ki-67. Although both CD4+ and CD8+ T cells proliferated spontaneously, the percentage of proliferating CD8+ T cells was 2 to 5 times higher than that of CD4+ T cells. In addition, more than 40% of HTLV-I Tax11-19–specific CD8+T cells as detected by an HLA-A*0201/Tax11-19 tetramer proliferated in culture. In spite of this expansion of HTLV-I–specific CD8+ T cells, HTLV-I proviral load did not decrease. This finding will help elucidate the dynamics of in vivo virus-host immunologic interactions that permit the coexistence of high HTLV-I–specific CD8+ cytotoxic T-lymphocyte responses and high HTLV-I proviral load in HAM/TSP.

scholarly journals Is human T–cell lymphotropic virus type I really silent?

2000 ◽  
Vol 355 (1400) ◽  
pp. 1013-1019 ◽  
Author(s):  
Becca Asquith ◽  
Emmanuel Hanon ◽  
Graham P. Taylor ◽  
Charles R. M. Bangham
Keyword(s):  
T Cell ◽  
Protein Expression ◽  
Virus Type ◽  
Peripheral Blood ◽  
Peripheral Blood Lymphocytes ◽  
Type I ◽  
Ctl Response ◽  
Blood Lymphocytes ◽  
Human T Cell

The role of the cellular immune response to human T–cell lymphotropic virus type I (HTLV–I) is not fully understood. The low level of HTLV–I protein expression in peripheral blood lymphocytes has led to the widely held belief that HTLV–I is transcriptionally silent in vivo . However, most HTLV–I–infected individuals mount a strong and persistently activated cytotoxic T–lymphocyte (CTL) response to the virus; this observation implies that there is abundant chronic transcription of HTLV–I genes. Here we show that HTLV–I Tax protein expression rises quickly in freshly isolated peripheral blood lymphocytes, but that expressing cells are rapidly killed by CTLs. Mathematical analysis of these results indicates that the CTL response is extremely efficient and that the half–life of a Tax–expressing cell is less than a day. We propose that HTLV–I protein expression in circulating lymphocytes is undetectable by current techniques because of the efficiency of the CTL–mediated immune surveillance in vivo .

scholarly journals Activation of T cell-derived lymphokine genes in T cells and fibroblasts: effects of human T cell leukemia virus type I p40xprotein and bovine papilloma virus encoded E2 protein

1988 ◽  
Vol 16 (14) ◽  
pp. 6547-6566 ◽  
Author(s):  
Shoichiro Miyatake ◽  
Motoharu Seiki ◽  
Rene DeWaal Malefijt ◽  
Toshio Heike ◽  
Jun-ichi Fujisawa ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Type ◽  
Leukemia Virus ◽  
Type I ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Papilloma Virus ◽  
Human T Cell ◽  
T Cell Leukemia Virus

Protective effect of interferon ? on human T cell leukaemia virus type I infection of CD4+ T cells isolated from human cord blood

1993 ◽  
Vol 37 (2) ◽  
pp. 97-104 ◽  
Author(s):  
Beatrice Macchi ◽  
Isabella Faraoni ◽  
Antonio Mastino ◽  
Chiara D'Onofrio ◽  
Gianna Romeo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protective Effect ◽  
Cord Blood ◽  
Virus Type ◽  
Cell Leukaemia ◽  
Type I ◽  
Human Cord Blood ◽  
Leukaemia Virus ◽  
Human T Cell

scholarly journals Human T-cell lymphotropic virus type I-transformed T-cells have a partial defect in ceramide synthesis in response to N-(4-hydroxyphenyl)retinamide

2005 ◽  
Vol 392 (1) ◽  
pp. 231-239 ◽  
Author(s):  
Nadine Darwiche ◽  
Ghada Abou-Lteif ◽  
Tarek Najdi ◽  
Lina Kozhaya ◽  
Ahmad Abou Tayyoun ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Growth Inhibition ◽  
Virus Type ◽  
De Novo ◽  
Type I ◽  
De Novo Synthesis ◽  
Human T Cell ◽  
Ceramide Synthesis ◽  
Malignant T Cells

Treatment with the synthetic retinoid HPR [N-(4-hydroxyphenyl)-retinamide] causes growth arrest and apoptosis in HTLV-I (human T-cell lymphotropic virus type-I)-positive and HTLV-I-negative malignant T-cells [8]. It was observed that HPR-mediated growth inhibition was associated with ceramide accumulation only in HTLV-I-negative cells. The aim of the present study was to investigate the mechanism by which HPR differentially regulates ceramide metabolism in HTLV-I-negative and HTLV-I-positive malignant T-cells. Clinically achievable concentrations of HPR caused early dose-dependent increases in ceramide levels only in HTLV-I-negative cells and preceded HPR-induced growth suppression. HPR induced de novo synthesis of ceramide in HTLV-I-negative, but not in HTLV-I-positive, cells. Blocking ceramide glucosylation in HTLV-I-positive cells, which leads to accumulation of endogenous ceramide, rendered these cells more sensitive to HPR. Exogenous cell-permeant ceramides that function partially by generating endogenous ceramide induced growth suppression in all tested malignant lymphocytes, were consistently found to be less effective in HTLV-I-positive cells confirming their defect in de novo ceramide synthesis. Owing to its multipotent activities, the HTLV-I-encoded Tax protein was suspected to inhibit ceramide synthesis. Tax-transfected Molt-4 and HELA cells were less sensitive to HPR and C6-ceramide mediated growth inhibition respectively and produced lower levels of endogenous ceramide. Together, these results indicate that HTLV-I-positive cells are defective in de novo synthesis of ceramide and that therapeutic modalities that bypass this defect are more likely to be successful.

AB0268 HUMAN T-CELL LEUKAEMIA VIRUS TYPE 1 MAY INVALIDATE T-SPOT.TB RESULTS AMONG RHEUMATOID ARTHRITIS PATIENTS: A RETROSPECTIVE OBSERVATIONAL STUDY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1432.1-1433
Author(s):  
K. Umekita ◽  
Y. Hashiba ◽  
R. Kudou ◽  
S. Miyauchi ◽  
M. Kimura ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Type ◽  
Peripheral Blood ◽  
Medical Records ◽  
Cell Leukaemia ◽  
Leukaemia Virus ◽  
Human T Cell ◽  
Ifn Γ

Background:In clinical rheumatology, interferon-γ release assays (IGRAs) have been reported as a useful diagnostic test for latent tuberculosis infection (LTBI) before beginning the administration of biologics such as anti-TNF therapies (1). CD4-positive T cells are the main target in Human T-cell leukaemia virus type 1 (HTLV-1) infection. Several reports suggest that the reaction of tuberculin skin test (TST) is attenuated in HTLV-1-positive individuals compared with that in HTLV-1-negative individuals (2). However, it remains unclear whether IGRAs are reliable for detecting TB infection among HTLV-1-positive RA patients.Objectives:The present study aimed to investigate the usefulness of the T-SPOT.TBassay in HTLV-1-positive RA patients. In addition, the association between the existence of IFN-γ producing T cells and HTLV-1 proviral loads (PVLs) in HTLV-1-positive RA patients was analysed on the basis of the T-SPOT.TBassay results.Methods:We reviewed the medical records of 75 HTLV-1-negative and 29 HTLV-1-positive RA patients were suspected cases of LTBI and evaluated using the T-SPOT.TBassay as a clinical practice from April 2012 to July 2019. The results of T-SPOT.TBwere collected from medical records, retrospectively. Peripheral blood samples were obtained from HTLV-1-positive RA patients for the analysis of HTLV-1 PVLs values. The study protocol was approved by the research ethics committees of our hospitals.Results:Approximately 55% of the HTLV-1-positive RA patients showed invalid results for the T-SPOT.TBassay (p < 0.0001); the cause of invalid results was a spot-forming count of >10 spots in the negative controls of the T-SPOT.TBassay among HTLV-1-positive RA patients. Among HTLV-1-positive RA patients, HTLV-1 PVL values were significantly higher in 16 patients who showed invalid results than in 13 patients who did not (p = 0.003). There were no between-group differences in female patient ratio, age, RA disease activity and therapeutic regimens. IFN-γ producing cells were detected in the peripheral blood of HTLV-1-positive RA patients without stimulation with TB-specific antigens.Conclusion:The incidence of invalid results for the T-SPOT.TBassay has been reported to be as low as 0.6% (3). The results of this assay for screening of LTBI in HTLV-1-positive RA patients should be interpreted with caution. Furthermore, our results show that an increase in IFN-γ producing T cell numbers due to HTLV-1 infection in RA patients may affect the pathogenesis of RA.References:[1]Iannone, F., et al.J. Rheumatol. Suppl.91, 41-46 (2014).[2]Tachibana, N., et al.Int. J. Cancer42, 829-831 (1988).[3]Rego, K., et al.Tuberculosis (Edinb.)108, 178-185 (2018).Acknowledgments:We would like to thank Dr Yuki Hashikura and Ms Yuki Kaseda of the University of Miyazaki for their technical support in this work. We would also like to acknowledge Ms Yumiko Kai at the Institute of Rheumatology, Zenjinkai Shimin-no-Mori Hospital, for her help in data management.A part this work was supported by a grant from the Practical Research Project for Rare/Intractable Diseases of the Japan Agency for Medical Research and Development (Grant No. JP19ek0109356), a Health and Labor Sciences Research Grant on Rare and Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan (Grant No. 19FC1007), and a Grant-in-Aid for Clinical Research from Miyazaki University Hospital.Disclosure of Interests:Kunihiko Umekita Paid instructor for: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Speakers bureau: Bristol-Myers Squibb, Yayoi Hashiba: None declared, Risa Kudou: None declared, Shunichi Miyauchi: None declared, Masatoshi Kimura: None declared, Motohiro Matsuda: None declared, Chihiro Iwao: None declared, Yumi Kariya: None declared, Takeshi Kawaguchi: None declared, Katoko Takajo: None declared, Koushou Iwao: None declared, Yuuki Rikitake: None declared, Ichiro Takajo: None declared, Toshihiko Hidaka Paid instructor for: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Speakers bureau: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Akihiko Okayama: None declared

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