HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells
Natsumi Araya, … , Steven Jacobson, Yoshihisa Yamano
Natsumi Araya, … , Steven Jacobson, Yoshihisa Yamano
Published June 24, 2014
Citation Information: J Clin Invest. 2014;124(8):3431-3442. https://doi.org/10.1172/JCI75250.
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Research Article Immunology

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

Abstract

Human T-lymphotropic virus type 1 (HTLV-1) is linked to multiple diseases, including the neuroinflammatory disease HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T cell leukemia/lymphoma. Evidence suggests that HTLV-1, via the viral protein Tax, exploits CD4+ T cell plasticity and induces transcriptional changes in infected T cells that cause suppressive CD4+CD25+CCR4+ Tregs to lose expression of the transcription factor FOXP3 and produce IFN-γ, thus promoting inflammation. We hypothesized that transformation of HTLV-1–infected CCR4+ T cells into Th1-like cells plays a key role in the pathogenesis of HAM/TSP. Here, using patient cells and cell lines, we demonstrated that Tax, in cooperation with specificity protein 1 (Sp1), boosts expression of the Th1 master regulator T box transcription factor (T-bet) and consequently promotes production of IFN-γ. Evaluation of CSF and spinal cord lesions of HAM/TSP patients revealed the presence of abundant CD4+CCR4+ T cells that coexpressed the Th1 marker CXCR3 and produced T-bet and IFN-γ. Finally, treatment of isolated PBMCs and CNS cells from HAM/TSP patients with an antibody that targets CCR4+ T cells and induces cytotoxicity in these cells reduced both viral load and IFN-γ production, which suggests that targeting CCR4+ T cells may be a viable treatment option for HAM/TSP.

Authors

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

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Figure 3

Tax and Sp1 cooperatively enhance TBX21 promoter activity.

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Tax and Sp1 cooperatively enhance TBX21 promoter activity. (A) Co-IP of ...
(A) Co-IP of endogenous Tax and Sp1. Nuclear extracts from MT-2 cells were immunoprecipitated with anti-Tax or anti–Sp1 antibodies or with normal IgG as a control, then immunoblotted with anti-Tax or anti-Sp1 antibodies as indicated. (B) Tax bound to the TBX21 promoter in vivo. ChIP assay using anti-Tax antibody followed by primers encompassing the TBX21 promoter region (–179 to –59) was performed on genomic DNA isolated from MT-2 cells. DNA (input) and IP with anti-Sp1 served as positive controls, and normal IgG served as a negative control. (C) Coactivation of TBX21 promoter by Sp1 and Tax. HEK293 cells were transfected with 100 ng of TBX21-Luc reporter plasmid or Sp1 expression plasmid, as well as 0–100 ng of Tax expression plasmid as indicated. Values were normalized to β-galactosidase activity as an internal control. Data are mean ± SD.