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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

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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 1

HTLV-1 mainly infects Tregs and inhibits their regulatory function.

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HTLV-1 mainly infects Tregs and inhibits their regulatory function.
(A) ...
(A) Higher HTLV-1 proviral DNA load in CD4+FOXP3+ cells (Tregs) compared with CD4+GATA3+ cells (P = 0.0020, Wilcoxon test) from asymptomatic carriers (AC; n = 6) and HAM/TSP patients (n = 4). PBMCs were FACS sorted, and proviral load was measured using quantitative PCR. Horizontal bars represent the mean value for each set. (B) Loss of regulatory function in Tax-expressing CD4+CD25+CCR4+ cells (Tregs). CD4+CD25– T cells from an HD were stimulated with CD2, CD3, and CD28 antibodies and cultured alone or in the presence of equal numbers of CD4+CD25+CCR4+ T cells, GFP lentivirus–infected HD CD4+CD25+CCR4+ T cells, or GFP-Tax lentivirus–infected HD CD4+CD25+CCR4+ T cells. As a control, CD4+CD25– T cells alone were cultured without any stimulus. Proliferation of T cells was determined using 3H-thymidine incorporation by adding 3H-thymidine for 16 hours after 4 days of culture. All tests were performed in triplicate. Data are mean ± SD. **P < 0.01, ***P < 0.001, ANOVA followed by Tukey test for multiple comparisons.

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