Visualization of HTLV-1–Specific Cytotoxic T Lymphocytes in the Spinal Cords of Patients With HTLV-1–Associated Myelopathy/Tropical Spastic Paraparesis

Matsuura, Eiji; Kubota, Ryuji; Tanaka, Yuetsu; Takashima, Hiroshi; Izumo, Shuji

doi:10.1097/nen.0000000000000141

Cited by 53 publications

(65 citation statements)

References 37 publications

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“…Pro‐inflammatory cytokines, such as tumor necrosis factor‐α, interferon (IFN)‐γ and interleukin (IL)‐1β, were detected in perivascular infiltrating cells . There is direct evidence that HTLV‐1‐infected CD4+ T cells have been observed within spinal cord lesions, and CD8+ T cells directed against HTLV‐1 antigens accumulate in the CSF and spinal cord lesions . Importantly, HTLV‐1 is only observed in T cell infiltrates within spinal cord lesions, but there is no convincing evidence showing that cells normally resident in the central nervous system (CNS) become infected .…”

Section: Ham/tsp Is Not a Simple Infection Of Cnsmentioning

confidence: 99%

“…Notably, more than half of the CXCR3+ T cells in the CSF of HAM/TSP patients are CD8+ T cells . It has been shown that CD8+ cytotoxic T lymphocytes, particularly HTLV‐1‐specific cytotoxic T lymphocytes, have a high potential for secreting IFN‐γ, and are abnormally elevated in the CSF and spinal cord lesions . Therefore, CXCL10 production by astrocytes might further boost the trafficking of CXCR3+ CCR4+ infected CD4+ T cells as well as CXCR3+ CD8+ cytotoxic T lymphocytes that secrete IFN‐γ, leading to a positive feedback inflammatory loop.…”

Section: Importance Of Cross‐talk Between Infected T Cells and Astrocmentioning

confidence: 99%

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How does human T‐lymphotropic virus type 1 cause central nervous system disease? The importance of cross‐talk between infected T cells and astrocytes

Yamano

2015

Clinical & Exp Neuroim

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Human T‐lymphotropic virus type 1 (HTLV‐1) can cause HTLV‐1‐associated myelopathy/tropical spastic paraparesis and adult T cell leukemia/lymphoma. The main feature of HTLV‐1‐associated myelopathy/tropical spastic paraparesis pathogenesis is a virus‐induced hyperactive immune response that causes chronic inflammation in the central nervous system (CNS), but the question remains: what is the mechanism by which HTLV‐1 deregulates the immune response and induce chronic inflammation? While T cell infiltrates in the CNS include HTLV‐1‐infected cells, HTLV‐1 does not appear to infect the neuronal cells themselves. It has been established that HTLV‐1 is a unique virus that mainly infects CD4+ helper T cells. We recently showed that HTLV‐1 heavily infects CCR4+ cells, which are known to include regulatory T cells. We showed that HTLV‐1 induces a Th1‐like state in these CCR4+ cells through T‐bet expression. We have also found that CXCL10 plays an important role in a positive feedback loop that maintains inflammation in the CNS. Astrocytes, which were shown to be the main producers of CXCL10 in the CNS, are another key player in the loop. To complete the picture, we showed that the infected CCR4+ Th1‐like T cells produce interferon‐γ, which is what stimulates astrocytes to produce CXCL10. Now we have a much better understanding of the molecular mechanisms at play in HTLV‐1‐associated myelopathy/tropical spastic paraparesis pathogenesis, and clearly CCR4+ cells are a significant contributor to the inflammatory pathways. Thus, we are currently carrying out a phase I/IIa clinical trial to test the effects and safety of a therapy that uses antibody‐dependent cell‐mediated cytotoxicity to target CCR4+ cells.

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Section: Ham/tsp Is Not a Simple Infection Of Cnsmentioning

confidence: 99%

Section: Importance Of Cross‐talk Between Infected T Cells and Astrocmentioning

confidence: 99%

How does human T‐lymphotropic virus type 1 cause central nervous system disease? The importance of cross‐talk between infected T cells and astrocytes

Yamano

2015

Clinical & Exp Neuroim

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“…This view of disease pathogenesis is most consistent with data generated from immunohistochemistry studies which demonstrate both CD4 (+) and CD8 (+) T lymphocytic infiltrates in spinal cord tissues during early stages of disease, with increasing dominance of CD8 (+) T lymphocytes and macrophages over the course of the illness (Umehara et al, 1993) (Abe et al, 1999) (Kubota et al, 1998). Recently, specific interactions between HTLV-1 Tax positive CD4 (+) T lymphocytes and virus-specific CTLs were demonstrated in spinal cord tissues of HAM/TSP patients using confocal laser scanning microscopy (Matsuura et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Dynamic acquisition of HTLV-1 tax protein by mononuclear phagocytes: Role in neurologic disease

Matsuura

Enose-Akahata

Yao

et al. 2017

Journal of Neuroimmunology

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Pathology of HTLV-1 associated myelopathy/Tropical spastic paraparesis (HAM/TSP) is believed to be the result of “bystander damage” involving effector CD8 (+) T lymphocytes (CTLs) killing of virus infected cells. But the specific cellular events leading up to tissue injury are still unclear. Here, we developed the Microscopy Imaging of Cytotoxic T lymphocyte assay with Fluorescence emission (MI-CaFé), an optimized visualization analysis to explore the interactions between CTLs and virus infected or viral antigen presenting target cells. Various cell-to-cell formations can be observed and our results demonstrate elevated frequencies of CTL-target cell conjugates in HAM/TSP patient PBMCs compared to control PBMCs. Furthermore, HTLV-1 Tax protein expression can be localized at the cell-cell junctions and also tracked moving from an infected cell to a CD14 (+) mononuclear phagocyte (MP). Activation of CD14 (+) MPs in HAM/TSP patient PBMCs and antigenic presentation of HTLV-1 Tax by MPs can be inferred by their spontaneous cytotoxicity after after 18 hours of in vitro culture. Given that CD4 (+) T lymphocytes are the primary reservoirs of HTLV-1 and MPs are scavenger cells responsible for pathogen clearance, spontaneous cytotoxicity against MPs in HAM/TSP PBMCs suggests a mechanism of chronic inflammation, secondary to low level of persistent virus infection within the central nervous system.

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“…13 CD4 + T lymphocytes are the predominant target of HTLV-1 infection, 14 which are early detected in spinal cord lesions. 15,16 Some research groups have shown that the risk for HAM/TSP development positively correlates with HTLV-1 proviral load in PBMCs. 17,18 The control of HTLV-1 infection in vivo has not been fully clarified yet.…”

mentioning

confidence: 99%

Phenotypic and functional changes in gamma delta T lymphocytes from HTLV-1 carriers

Albuquerque

Granato

Castro

et al. 2019

Journal of Leukocyte Biology

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Human T‐cell lymphotropic virus type‐1 (HTLV‐1) is the etiologic agent of HTLV‐1‐associated myelopathy/tropical spastic paraparesis (HAM/TSP), which is a chronic inflammatory disease that leads to gradual loss of motor movement as a result of the death of spinal cord cells through immune mediated mechanisms. The risk to develop HAM/TSP disease positively correlates with the magnitude of HTLV‐1 proviral load. Gamma‐delta T lymphocytes have been recognized as important players in a variety of infectious diseases. Therefore, we have investigated interactions between HTLV‐1 infection and γδ T lymphocytes during HAM/TSP. Similar frequencies of total γδ T lymphocytes and their Vγ9δ2+ and Vγ9δ2neg subpopulations were observed in HAM/TSP patients. However, T lymphocytes obtained from HTLV‐1 carriers displayed significantly higher rates of spontaneous proliferation and NKp30 expression when compared to cells from uninfected donors. In addition, an important decrease in the frequency of granzyme B+ γδ T lymphocytes (approximately 50%) was observed in HAM/TSP patients. Higher proportion of IFN‐γ+ γδ T lymphocytes was found in HTLV‐1‐infected patients, which positively correlated with the HTLV‐1 proviral load in peripheral blood mononuclear cells. Collectively, our data indicates that HTLV‐1 infection leads to phenotypic and functional changes in the population of γδ T lymphocyte population, suggesting that HTLV‐1 infection modulates functions associated to these cells, which might be involved in controlling the infection or in the development of HTLV‐1‐associated diseases.

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Visualization of HTLV-1–Specific Cytotoxic T Lymphocytes in the Spinal Cords of Patients With HTLV-1–Associated Myelopathy/Tropical Spastic Paraparesis

Abstract: Supplemental digital content is available in the text.

Cited by 53 publications

References 37 publications

How does human T‐lymphotropic virus type 1 cause central nervous system disease? The importance of cross‐talk between infected T cells and astrocytes

How does human T‐lymphotropic virus type 1 cause central nervous system disease? The importance of cross‐talk between infected T cells and astrocytes

Dynamic acquisition of HTLV-1 tax protein by mononuclear phagocytes: Role in neurologic disease

Phenotypic and functional changes in gamma delta T lymphocytes from HTLV-1 carriers

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