المؤلفون: Yoshihisa Yamano, Katsunori Takahashi, Utano Tomaru, Ariella Coler-Reilly, Tomoo Sato, Hitoshi Ando, Steven Jacobson, Mari Yoshida, Naoko Yagishita, Atsuhiko Hasegawa, Toshihiro Nakajima, Mari Kannagi, Yasuhiro Hasegawa, Natsumi Araya, Kusuki Nishioka, Yuetsu Tanaka, Yasuo Kunitomo, Junji Yamauchi, Atae Utsunomiya

المصدر: Journal of Clinical Investigation. 124:3431-3442

مصطلحات موضوعية: Adult, CD4-Positive T-Lymphocytes, Cytotoxicity, Immunologic, Male, Receptors, CCR4, Sp1 Transcription Factor, medicine.medical_treatment, CXCR3, T-Lymphocytes, Regulatory, Cell Line, Interferon-gamma, Interleukin 21, immune system diseases, hemic and lymphatic diseases, medicine, Humans, Interferon gamma, Aged, Human T-lymphotropic virus 1, Sp1 transcription factor, biology, Antibodies, Monoclonal, virus diseases, hemic and immune systems, Gene Products, tax, General Medicine, Immunotherapy, Middle Aged, Th1 Cells, Viral Load, biology.organism_classification, Virology, Molecular biology, Paraparesis, Tropical Spastic, Cell culture, biology.protein, Female, Antibody, T-Box Domain Proteins, Research Article, medicine.drug

الوصف: 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.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e7897603ec8ccf67ec04f53d0f734587Test
https://doi.org/10.1172/jci75250Test

المؤلفون: Natsumi Araya¹, Tomoo Sato¹, Hitoshi Ando¹, Utano Tomaru², Mari Yoshida³, Coler-Reilly, Ariella¹, Naoko Yagishita¹, Junji Yamauchi¹, Atsuhiko Hasegawa⁴, Mari Kannagi⁴, Yasuhiro Hasegawa⁵, Katsunori Takahashi¹, Yasuo Kunitomo¹, Yuetsu Tanaka⁶, Toshihiro Nakajima^7,8, Kusuki Nishioka⁷, Atae Utsunomiya⁹, Jacobson, Steven¹⁰, Yoshihisa Yamano¹ yyamano@marianna-u.ac.jp

المصدر: Journal of Clinical Investigation. Aug2014, Vol. 124 Issue 8, p3431-3442. 12p. 1 Color Photograph, 4 Graphs.

مصطلحات موضوعية: *HTLV-I, *CD4 antigen, *T cells, *TH1 cells, *VIRAL proteins, *SPINAL cord

مستخلص: 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. [ABSTRACT FROM AUTHOR]