title: 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
authors: N
authors: Araya
authors: Tomoo
authors: T
authors: Sato
authors: Hitoshi
authors: H
authors: Ando
authors: Utano
authors: U
authors: Tomaru
authors: Mari
authors: M
authors: Yoshida
authors: Ariella
authors: A
authors: Coler-Reilly
authors: Naoko
authors: N
authors: Yagishita
authors: Junji
authors: J
authors: Yamauchi
authors: Atsuhiko
authors: A
authors: Hasegawa
authors: Mari
authors: M
authors: Kannagi
authors: Yasuhiro
authors: Y
authors: Hasegawa
authors: Katsunori
authors: K
authors: Takahashi
authors: Yasuo
authors: Y
authors: Kunitomo
authors: Yuetsu
authors: Y
authors: Tanaka
authors: Toshihiro
authors: T
authors: Nakajima
authors: Kusuki
authors: K
authors: Nishioka
authors: Atae
authors: A
authors: Utsunomiya
authors: Steven
authors: S
authors: Jacobson
authors: Yoshihisa
authors: Y
authors: Yamano
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D005260:Female; D016356:Gene Products, tax / Q000276:immunology; D015368:Human T-lymphotropic virus 1 / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015493:Paraparesis, Tropical Spastic / Q000235:genetics / Q000276:immunology / Q000821:virology; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000276:immunology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000821:virology; D018417:Th1 Cells / Q000276:immunology* / Q000821:virology*; D019562:Viral Load / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: D000911:Antibodies, Monoclonal; C515354:CCR4 protein, human; D016356:Gene Products, tax; D054398:Receptors, CCR4; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C514970:tax protein, Human T-lymphotrophic virus 1; D007371:Interferon-gamma