HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells

J Clin Invest. 2014 Aug;124(8):3431-42. doi: 10.1172/JCI75250. Epub 2014 Jun 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Antibodies, Monoclonal
  • CCR4 protein, human
  • Gene Products, tax
  • Receptors, CCR4
  • Sp1 Transcription Factor
  • Sp1 protein, human
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • tax protein, Human T-lymphotrophic virus 1
  • Interferon-gamma