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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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.