Breakdown in repression of IFN-γ mRNA leads to accumulation of self-reactive effector CD8+ T cells

J Immunol. 2012 Jul 15;189(2):701-10. doi: 10.4049/jimmunol.1102432. Epub 2012 Jun 8.

Abstract

Tight regulation of virus-induced cytotoxic effector CD8(+) T cells is essential to prevent immunopathology. Naturally occurring effector CD8(+) T cells, with a KLRG1(hi) CD62L(lo) phenotype typical of short-lived effector CD8(+) T cells (SLECs), can be found in increased numbers in autoimmune-prone mice, most notably in mice homozygous for the san allele of Roquin. These SLEC-like cells were able to trigger autoimmune diabetes in a susceptible background. When Roquin is mutated (Roquin(san)), effector CD8(+) T cells accumulate in a cell-autonomous manner, most prominently as SLEC-like effectors. Excessive IFN-γ promotes the accumulation of SLEC-like cells, increases their T-bet expression, and enhances their granzyme B production in vivo. We show that overexpression of IFN-γ was caused by failed posttranscriptional repression of Ifng mRNA. This study identifies a novel mechanism that prevents accumulation of self-reactive cytotoxic effectors, highlighting the importance of regulating Ifng mRNA stability to maintain CD8(+) T cell homeostasis and prevent CD8-mediated autoimmunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / transplantation
  • Cell Aggregation / genetics
  • Cell Aggregation / immunology*
  • Cellular Senescence / genetics
  • Cellular Senescence / immunology
  • Cytotoxicity, Immunologic* / genetics
  • Down-Regulation / genetics
  • Down-Regulation / immunology*
  • Homeostasis / genetics
  • Homeostasis / immunology
  • Immunosuppressive Agents / antagonists & inhibitors
  • Immunosuppressive Agents / metabolism
  • Interferon-gamma / antagonists & inhibitors*
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / genetics*
  • Lectins, C-Type / biosynthesis
  • Lectins, C-Type / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation / immunology
  • RNA Stability / immunology
  • RNA, Messenger / antagonists & inhibitors*
  • RNA, Messenger / genetics
  • Receptors, Immunologic
  • Trans-Activators / biosynthesis
  • Trans-Activators / genetics
  • Ubiquitin-Protein Ligases / genetics

Substances

  • Immunosuppressive Agents
  • KLRG1 protein, human
  • Lectins, C-Type
  • RNA, Messenger
  • Receptors, Immunologic
  • Trans-Activators
  • Interferon-gamma
  • Rc3h1 protein, mouse
  • Ubiquitin-Protein Ligases

Associated data

  • GEO/GSE37319