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

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.

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

Blood ◽

10.1182/blood.v98.6.1858 ◽

2001 ◽

Vol 98 (6) ◽

pp. 1858-1861 ◽

Cited By ~ 94

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.

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

Blood ◽

10.1182/blood-2008-02-138529 ◽

2008 ◽

Vol 112 (6) ◽

pp. 2400-2410 ◽

Cited By ~ 25

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.

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Defective Human T-Cell Lymphotropic Virus Type I (HTLV-I) Provirus in 10 Chilean Seronegative Patients with Tropical Spastic Paraparesis or HTLV-I-Associated Myelopathy

Journal of Clinical Microbiology ◽

10.1128/jcm.36.6.1811-1813.1998 ◽

1998 ◽

Vol 36 (6) ◽

pp. 1811-1813 ◽

Cited By ~ 10

Author(s):

Eugenio Ramirez ◽

Luis Cartier ◽

Maritza Rios ◽

Jorge Fernandez

Keyword(s):

T Cell ◽

Virus Type ◽

Peripheral Blood Mononuclear Cells ◽

Mononuclear Cells ◽

Spastic Paraparesis ◽

Tropical Spastic Paraparesis ◽

Type I ◽

Peripheral Blood Mononuclear ◽

Human T Cell ◽

Blood Mononuclear Cells

We studied the presence of tax and ltrgenes from human T-cell lymphotropic virus type I (HTLV-I) provirus in the peripheral blood mononuclear cells from 15 seronegative patients with tropical spastic paraparesis or HTLV-I-associated myelopathy by PCR. Only a region of the tax gene from 10 patients was amplified. The nucleotide homologies of six Chilean isolates to the ATK-1 clone ranged between 98.7 and 99.4%.

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Differential activation of proliferation and cytotoxicity in human T-cell lymphotropic virus type I Tax-specific CD8 T cells by an altered peptide ligand.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.92.9.4036 ◽

1995 ◽

Vol 92 (9) ◽

pp. 4036-4040 ◽

Cited By ~ 34

Author(s):

P. Hollsberg ◽

W. E. Weber ◽

F. Dangond ◽

V. Batra ◽

A. Sette ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Virus Type ◽

Cd8 T Cells ◽

Peptide Ligand ◽

Altered Peptide Ligand ◽

Type I ◽

Differential Activation ◽

Human T Cell

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Recurrent Facial Erythema with Cytotoxic T Cell Infiltration as a Possible Reactive Eruption in a Human T-Cell Lymphotropic Virus Type 1 Carrier

Case Reports in Dermatology ◽

10.1159/000430804 ◽

2015 ◽

Vol 7 (2) ◽

pp. 95-99 ◽

Cited By ~ 2

Author(s):

Yasuhiro Kaneko ◽

Kazuki Tatsuno ◽

Toshiharu Fujiyama ◽

Taisuke Ito ◽

Yoshiki Tokura

Keyword(s):

T Cells ◽

T Cell ◽

Virus Type ◽

Cd8 T Cells ◽

Spastic Paraparesis ◽

Cytotoxic T Cell ◽

Neoplastic Cells ◽

Adult T Cell Leukemia ◽

Human T Cell

Human T-cell lymphotropic virus type 1 (HTLV-1) induces adult T cell leukemia/lymphoma (ATLL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and carrier. Approximately half of ATLL patients have direct skin involvement of neoplastic cells. However, there exist HTLV-1-associated reactive eruptions with a predominant infiltrate of non-neoplastic CD8+ T cells in ATLL, HAM/TSP and carrier. A 50-year-old Japanese female HTLV-1 carrier had several episodes of itchy, indurated erythema that occurred diffusely on the face and neck, lasted for 2 weeks and spontaneously subsided without sequelae. Histopathologically, CD3+ T cells infiltrated the upper dermis, and part of the infiltrating cells were CD4+CD25+, sharing the phenotype with ATLL neoplastic cells. An aggregate of CD8+ T cells bearing the cytotoxic molecule TIA-1 was also present. It is possible that skin-affinitive HTLV-1+CD4+ T cells propagated and subsequently disappeared as a result of cytotoxic T cell attack.

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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 ◽

10.1182/blood.v95.4.1386.004k22_1386_1392 ◽

2000 ◽

Vol 95 (4) ◽

pp. 1386-1392 ◽

Cited By ~ 185

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.

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Class I–unrestricted noncytotoxic anti–HTLV-I activity of CD8+ T cells

Blood ◽

10.1182/blood.v96.5.1994 ◽

2000 ◽

Vol 96 (5) ◽

pp. 1994-1995 ◽

Cited By ~ 5

Author(s):

Masako Moriuchi ◽

Hiroyuki Moriuchi

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Mononuclear Cells ◽

Membrane Filter ◽

Cd8 T Cell ◽

Class I ◽

Type I ◽

Peripheral Blood Mononuclear ◽

Permeable Membrane

Abstract Although it is widely believed that viral clearance is mediated principally by the destruction of infected cells by cytotoxic T cells, noncytolytic antiviral activity of CD8+ T cells may play a role in preventing the progression to disease in infections with immunodeficiency viruses and hepatitis B virus. We demonstrate here that (1) replication of human T-lymphotropic virus type I (HTLV-I) is more readily detected from CD8+ T-cell–depleted (CD8−) peripheral blood mononuclear cells (PBMCs) of healthy HTLV-I carriers than from unfractionated PBMCs, (2) cocultures of CD8− PBMCs with autologous or allogeneic CD8+ T cells suppressed HTLV-I replication, and (3) CD8+ T-cell anti-HTLV-I activity is not abrogated intrans-well cultures in which CD8+ cells are separated from CD8− PBMCs by a permeable membrane filter. These results suggest that class I-unrestricted noncytolytic anti–HTLV-I activity is mediated, at least in part by a soluble factor(s), and may play a role in the pathogenesis of HTLV-I infection.

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