TY - JOUR AU - Araya, Natsumi AU - Sato, Tomoo AU - Ando, Hitoshi AU - Tomaru, Utano AU - Yoshida, Mari AU - Coler-Reilly, Ariella AU - Yagishita, Naoko AU - Yamauchi, Junji AU - Hasegawa, Atsuhiko AU - Kannagi, Mari AU - Hasegawa, Yasuhiro AU - Takahashi, Katsunori AU - Kunitomo, Yasuo AU - Tanaka, Yuetsu AU - Nakajima, Toshihiro AU - Nishioka, Kusuki AU - Utsunomiya, Atae AU - Jacobson, Steven AU - Yamano, Yoshihisa T1 - HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells PY - 2014/08/01/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI75250 VL - 124 IS - 8 UR - https://doi.org/10.1172/JCI75250 SP - 3431 EP - 3442 PB - The American Society for Clinical Investigation ER -