HTLV-1 induces T cell malignancy and inflammation by viral antisense factor-mediated modulation of the cytokine signaling

Proc Natl Acad Sci U S A. 2020 Jun 16;117(24):13740-13749. doi: 10.1073/pnas.1922884117. Epub 2020 May 29.

Abstract

Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of a T cell neoplasm and several inflammatory diseases. A viral gene, HTLV-1 bZIP factor (HBZ), induces pathogenic Foxp3-expressing T cells and triggers systemic inflammation and T cell lymphoma in transgenic mice, indicating its significance in HTLV-1-associated diseases. Here we show that, unexpectedly, a proinflammatory cytokine, IL-6, counteracts HBZ-mediated pathogenesis. Loss of IL-6 accelerates inflammation and lymphomagenesis in HBZ transgenic mice. IL-6 innately inhibits regulatory T cell differentiation, suggesting that IL-6 functions as a suppressor against HBZ-associated complications. HBZ up-regulates expression of the immunosuppressive cytokine IL-10. IL-10 promotes T cell proliferation only in the presence of HBZ. As a mechanism of growth promotion by IL-10, HBZ interacts with STAT1 and STAT3 and modulates the IL-10/JAK/STAT signaling pathway. These findings suggest that HTLV-1 promotes the proliferation of infected T cells by hijacking the machinery of regulatory T cell differentiation. IL-10 induced by HBZ likely suppresses the host immune response and concurrently promotes the proliferation of HTLV-1 infected T cells.

Keywords: HBZ; HTLV-1; IL-10; IL-6; JAK/STAT signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / immunology*
  • Cell Differentiation
  • Cell Proliferation
  • HTLV-I Infections / genetics
  • HTLV-I Infections / immunology*
  • HTLV-I Infections / pathology
  • HTLV-I Infections / virology
  • Host-Pathogen Interactions
  • Human T-lymphotropic virus 1 / genetics
  • Human T-lymphotropic virus 1 / immunology*
  • Human T-lymphotropic virus 1 / physiology
  • Humans
  • Interleukin-10 / genetics
  • Interleukin-10 / immunology
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology*
  • Lymphoma / genetics
  • Lymphoma / immunology
  • Lymphoma / pathology
  • Lymphoma / virology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Retroviridae Proteins / genetics
  • Retroviridae Proteins / immunology*
  • T-Lymphocytes, Regulatory / immunology

Substances

  • Basic-Leucine Zipper Transcription Factors
  • HBZ protein, human T-cell leukemia virus type I
  • Interleukin-6
  • Retroviridae Proteins
  • Interleukin-10