Expression of the DNA-Binding Factor TOX Promotes the Encephalitogenic Potential of Microbe-Induced Autoreactive CD8 + T Cells

Immunity. 2018 May 15;48(5):937-950.e8. doi: 10.1016/j.immuni.2018.04.005.

Abstract

Infections are thought to trigger CD8+ cytotoxic T lymphocyte (CTL) responses during autoimmunity. However, the transcriptional programs governing the tissue-destructive potential of CTLs remain poorly defined. In a model of central nervous system (CNS) inflammation, we found that infection with lymphocytic choriomeningitis virus (LCMV), but not Listeria monocytogenes (Lm), drove autoimmunity. The DNA-binding factor TOX was induced in CTLs during LCMV infection and was essential for their encephalitogenic properties, and its expression was inhibited by interleukin-12 during Lm infection. TOX repressed the activity of several transcription factors (including Id2, TCF-1, and Notch) that are known to drive CTL differentiation. TOX also reduced immune checkpoint sensitivity by restraining the expression of the inhibitory checkpoint receptor CD244 on the surface of CTLs, leading to increased CTL-mediated damage in the CNS. Our results identify TOX as a transcriptional regulator of tissue-destructive CTLs in autoimmunity, offering a potential mechanistic link to microbial triggers.

Keywords: Listeria monocytogenes; T cell differentiation; autoimmunity; cytotoxic T cells; experimental autoimmune encephalomyelitis; lymphocytic choriomeningitis virus; multiple sclerosis; thymocyte selection-associated high-mobility group box factor; transcription factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Autoimmunity / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / virology
  • Female
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / immunology*
  • Homeodomain Proteins / metabolism
  • Humans
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology*
  • Lymphocytic choriomeningitis virus / physiology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Signaling Lymphocytic Activation Molecule Family / immunology
  • T-Lymphocytes, Cytotoxic / immunology

Substances

  • Cd244a protein, mouse
  • Homeodomain Proteins
  • Rhox8 protein, mouse
  • Signaling Lymphocytic Activation Molecule Family