HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells
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
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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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 4

HTLV-1–infected Th1-like CCR4+ cells invade the CNS of HAM/TSP patients.

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HTLV-1–infected Th1-like CCR4+ cells invade the CNS of HAM/TSP patients....
(A) Detection of CCR4+ cells expressing T-bet, IFN-γ, and CXCR3 infiltrating the spinal cord of a HAM/TSP patient. Representative images show immunofluorescent codetection of CCR4 with T-bet, IFN-γ, and CXCR3, as well as the merged images, in thoracic spinal cord sections. Rabbit and goat IgG antibody served as a negative control. Scale bars: 20 μm. (B) Presence of HTLV-1–infected CCR4+ cells in HAM/TSP patient CSF. Representative images show immunofluorescence-FISH codetection of CCR4 (green) and HTLV-1 provirus (red) in Jurkat cells (uninfected control), MT-2 cells (infected control), and CSF cells from the patients. Arrows denote red provirus signal in the CSF sample. Scale bars: 20 μm. (C) CD4+ T cells in HAM/TSP patient CSF were mostly CCR4+CXCR3+. A dot plot of CCR4 and CXCR3 expression in CD4+ gated cells isolated from the CSF of a representative HAM/TSP patient is shown. (D) CD4+CCR4+CXCR3+ cells were numerous in CSF, but not elevated in peripheral blood, of HAM/TSP patients. Graphs show the percentages of CCR4–CXCR3–, CCR4–CXCR3+, CCR4+CXCR3– and CCR4+CXCR3+ T cells among CD4+ PBMCs and CSF cells from HAM/TSP patients (n = 8) and PBMCs from HDs (n = 4). Analysis was performed using FACS. Data are mean ± SD. (E) Proliferation was not observed in CD4+CCR4+CXCR3+ cells from HAM/TSP patient CSF. The rate of Ki67 expression, a marker for cell proliferation, is shown for CD4+CCR4+CXCR3+ gated cells from the CSF of a representative HAM/TSP patient.