Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs

J Exp Med. 2009 Jan 16;206(1):51-9. doi: 10.1084/jem.20081242. Epub 2009 Jan 12.

Abstract

Activation of naive CD8(+) T cells with antigen induces their differentiation into effector cytolytic T lymphocytes (CTLs). CTLs lyse infected or aberrant target cells by exocytosis of lytic granules containing the pore-forming protein perforin and a family of proteases termed granzymes. We show that effector CTL differentiation occurs in two sequential phases in vitro, characterized by early induction of T-bet and late induction of Eomesodermin (Eomes), T-box transcription factors that regulate the early and late phases of interferon (IFN) gamma expression, respectively. In addition, we demonstrate a critical role for the transcription factor Runx3 in CTL differentiation. Runx3 regulates Eomes expression as well as expression of three cardinal markers of the effector CTL program: IFN-gamma, perforin, and granzyme B. Our data point to the existence of an elaborate transcriptional network in which Runx3 initially induces and then cooperates with T-box transcription factors to regulate gene transcription in differentiating CTLs.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Northern
  • Blotting, Western
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Core Binding Factor Alpha 3 Subunit / genetics
  • Core Binding Factor Alpha 3 Subunit / physiology*
  • Cytotoxicity, Immunologic / immunology
  • Gene Expression Regulation*
  • Granzymes / genetics
  • Granzymes / metabolism
  • Interferon-gamma / metabolism
  • Interleukin-2 / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Biological
  • Perforin / genetics
  • Perforin / metabolism
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism
  • T-Box Domain Proteins / physiology*
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Core Binding Factor Alpha 3 Subunit
  • Eomes protein, mouse
  • Interleukin-2
  • Receptors, Antigen, T-Cell, alpha-beta
  • Runx3 protein, mouse
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Tumor Necrosis Factor-alpha
  • Perforin
  • Interferon-gamma
  • Granzymes