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 5

CCR4 shows potential as a molecular target for HAM/TSP immunotherapy.

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CCR4 shows potential as a molecular target for HAM/TSP immunotherapy. (A...
(A–G) Cells isolated from HAM/TSP patients were sorted via FACS (A; n = 7) or cultured for 7 days under the following conditions: PBMCs were cultured with various concentrations of KM2760 or 1 μg/ml PSL (B–E; n = 9), and CSF cells were cultured with 1 μg/ml KM2760 (F and G; n = 8). (A, C, and F) HTLV-1 proviral DNA loads were measured using quantitative PCR. (D) Degree of spontaneous proliferation was assessed by measuring 3H-thymidine incorporation. (E and G) IFN-γ production in the culture media was evaluated using CBA assays. HTLV-1 resided in CD4+CCR4+ rather than CCR4– cells among PBMCs (A), and KM2760 treatment effectively targeted these cells (B). Consequently, KM2760 treatment successfully reduced HTLV-1 proviral DNA load (C), suppressed spontaneous proliferation (D), and decreased IFN-γ production (E) in PBMC cultures as well as reducing HTLV-1 DNA load (F) and IFN-γ production (G) in CSF cell cultures derived from HAM/TSP patients. (A and C–E) Data are mean ± SD. (B, F, and G) Thick horizontal bars represent mean value for all patients; line segments represent individual patients. Statistical analyses were performed using Friedman test followed by Dunn test for multiple comparisons (C–E) or Wilcoxon test (A, B, F, and G). *P < 0.05, **P < 0.01, ***P < 0.001 vs. untreated control.