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

• Published in: The Journal of experimental medicine 2009-01, Vol.206 (1), p.51-59
• Main Authors: Cruz-Guilloty, Fernando, Pipkin, Matthew E, Djuretic, Ivana M, Levanon, Ditsa, Lotem, Joseph, Lichtenheld, Mathias G, Groner, Yoram, Rao, Anjana
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Northern; Blotting, Western; Brief Definitive Reports; 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
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20081242

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.