RRC ID 34731
Author Araya N, Sato T, Ando H, Tomaru U, Yoshida M, Coler-Reilly A, Yagishita N, Yamauchi J, Hasegawa A, Kannagi M, Hasegawa Y, Takahashi K, Kunitomo Y, Tanaka Y, Nakajima T, Nishioka K, Utsunomiya A, Jacobson S, Yamano Y.
Title HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells.
Journal J Clin Invest
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.
Volume 124(8)
Pages 3431-42
Published 2014-8-1
DOI 10.1172/JCI75250
PII 75250
PMID 24960164
PMC PMC4109535
MeSH Adult Aged Antibodies, Monoclonal / therapeutic use CD4-Positive T-Lymphocytes / immunology* CD4-Positive T-Lymphocytes / virology* Cell Line Cytotoxicity, Immunologic Female Gene Products, tax / immunology Human T-lymphotropic virus 1 / immunology* Human T-lymphotropic virus 1 / pathogenicity* Humans Immunotherapy Interferon-gamma / biosynthesis Interferon-gamma / genetics Male Middle Aged Paraparesis, Tropical Spastic / genetics Paraparesis, Tropical Spastic / immunology Paraparesis, Tropical Spastic / virology Receptors, CCR4 / antagonists & inhibitors Receptors, CCR4 / immunology Receptors, CCR4 / metabolism* Sp1 Transcription Factor / immunology T-Box Domain Proteins / genetics T-Box Domain Proteins / immunology T-Lymphocytes, Regulatory / immunology T-Lymphocytes, Regulatory / virology Th1 Cells / immunology* Th1 Cells / virology* Viral Load / immunology
IF 11.864
Times Cited 50
DNA material CSII-CMV-MCS (RDB04377)