HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells

Araya, Natsumi; Sato, Tomoo; Ando, Hitoshi; Tomaru, Utano; Yoshida, Mari; Coler‐Reilly, Ariella; Yagishita, Naoko; Yamauchi, Junji; Hasegawa, Atsuhiko; Kannagi, Mari; Hasegawa, Yasuhiro; Takahashi, Katsunori; Kunitomo, Yasuo; Tanaka, Yuetsu; Nakajima, Takeshi; Nishioka, Kusuki; Utsunomiya, Atae; Jacobson, Steven; Yamano, Yoshihisa

doi:10.1172/jci75250

Cited by 93 publications

(108 citation statements)

References 60 publications

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“…In addition, in mouse models of multiple sclerosis and inflammatory bowel disease, the transition of T H 17 cells to a T H 1 or mixed T H 17/T H 1 cell phenotype is necessary to drive the disease 19,25,122,170,171 . In patients with human T cell leukaemia virus type 1 (HTLV1)-associated myelopathy (also known as tropical spastic para paresis), a neuroinflammatory disorder with multiple sclerosis-like symptoms resulting from infection with HTLV1, the virus is most likely to drive disease by selectively infecting T Reg cells and converting them into IFNγ-producing T H 1-like cells by the direct induction of T-bet expression by virally encoded proteins 172 . Thus, T cell plasticity is an important factor in immunological diseases, and the capacity to control T cell programming could lead to new therapies that ameliorate disease by preventing deleterious, or promoting desirable, T cell functions.…”

Section: Micrornasmentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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| CD4 + T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4 + T cell plasticity by examining the molecular mechanisms that regulate it -from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

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Section: Micrornasmentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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“…Paradoxically, despite the presence of infected Tregs in HAM/TSP as well, isolated HAM/SP patient Tregs do not suppress the activation of Teffs and instead have been shown to be pro-inflammatory (Araya et al, 2014;. This suggests that the previous observations of decreased FoxP3 mRNA expression that occurred with Tax transfection was due to reduced demethylation of the FoxP3 TSDR.…”

Section: Discussion and Future Directions Discussionmentioning

confidence: 93%

“…Induction of pTregs might explain why HTLV-1 infected Tregs are more prone to convert to IFN- producing cells and also might explain the reduced levels of TSDR demethylation detected (Anderson et al, 2016; did not show altered suppression of Teffs (Araya et al, 2014). Initial experiments shown in Chapter 2 suggests that this reduced proliferation is due to a reduction in TSDR demethylation, although it is too early to conclude that this was a result of HTLV-1 specific genes.…”

Section: Discussion and Future Directions Discussionmentioning

confidence: 99%

“…Furthermore, transduction of Tax into CD4 + CD25 + T cells resulted in reduced suppression of proliferating allogeneic effector T cells (Teffs) (Araya et al, 2014 (Tamburro et al, 2011). This allows isolation of concentrated exosomes from as little as 250L of human biological fluid (Jaworski et al, 2014b).…”

Section: Project Rationalementioning

confidence: 99%

“…Indeed, the CD4 + CD25 + subset, in which Tregs reside, serves as the dominant reservoir for HTLV-1 in HAM/TSP patients . The Tregs isolated from HAM/TSP patients are less able to reduce proliferation of allogeneic ND Teffs cells (Araya et al, 2014; . Interestingly, Tax has been shown to interfere with gene expression through binding to epigenetic modulators and binding directly to promoters (Bogenberger and Laybourn, 2008;Cheng et al, 2007;Ego et al, 2005).…”

Section: Tregs In Ham/tspmentioning

confidence: 99%

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The Role of HTLV-1 in Alteration of Immune Regulation Through Regulatory T Cell Dysfunction and Exosomal Manipulation

Anderson

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Clinical trial of a humanized anti‐IL‐2/IL‐15 receptor β chain in HAM/TSP

Enose-Akahata

Ohayon

et al. 2019

Ann Clin Transl Neurol

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Objective Human T cell lymphotropic virus 1 (HTLV‐1)‐associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive, neurological disease. Chronic activation of CD8+ T cells, as evidenced by increased spontaneous lymphoproliferation and HTLV‐1‐specific cytotoxic T cells, has been demonstrated in HAM/TSP patients. Since IL‐2 and IL‐15 stimulate memory CD8+ T cell activity, these cytokines have been implicated in the immunopathogenesis of HAM/TSP. In this phase I trial, we evaluated the safety, pharmacokinetics, and ability of Hu‐Mikβ1, a humanized monoclonal antibody directed toward the IL‐2/IL‐15 receptor β‐chain (IL‐2/IL‐15Rβ: CD122), to saturate CD122 and regulate abnormal immune responses in patients with HAM/TSP by inhibition of IL‐15 action. Methods Hu‐Mikβ1 was administered intravenously at doses of 0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg in a total of nine HAM/TSP patients. Five doses of Hu‐Mikβ1 were administered at 3‐week intervals. The clinical response was evaluated using standardized scales. Viral and immunologic outcome measures were examined including HTLV‐1 proviral load, T cell phenotypic analysis and spontaneous lymphoproliferation in HAM/TSP patients. Results There was no significant toxicity associated with Hu‐Mikβ1 administration in HAM/TSP patients. Saturation of CD122 by Hu‐Mikβ1 was achieved in five out of nine HAM/TSP patients. Administration of Hu‐Mikβ1 was associated with inhibition of aberrant CD8+ T cell function including spontaneous lymphoproliferation and degranulation and IFN‐γ expression, especially in HAM/TSP patients that achieved CD122 saturation. Interpretation The treatment with Hu‐Mikβ1 had a number of immunological effects on HAM/TSP patients although no clinical efficacy was observed. We also did not see any dose‐related toxicity.

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HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells

Cited by 93 publications

References 60 publications

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

The Role of HTLV-1 in Alteration of Immune Regulation Through Regulatory T Cell Dysfunction and Exosomal Manipulation

Clinical trial of a humanized anti‐IL‐2/IL‐15 receptor β chain in HAM/TSP

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