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

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.
PMID
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Authors

Mayor MeshTerms

Gene Expression Regulation

Keywords
Journal Title the journal of experimental medicine
Publication Year Start




PMID- 19139168
OWN - NLM
STAT- MEDLINE
DCOM- 20090223
LR  - 20161122
IS  - 1540-9538 (Electronic)
IS  - 0022-1007 (Linking)
VI  - 206
IP  - 1
DP  - 2009 Jan 16
TI  - Runx3 and T-box proteins cooperate to establish the transcriptional program of
      effector CTLs.
PG  - 51-9
LID - 10.1084/jem.20081242 [doi]
AB  - 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.
FAU - Cruz-Guilloty, Fernando
AU  - Cruz-Guilloty F
AD  - Harvard Medical School and the Immune Disease Institute, Boston, MA 02115, USA.
FAU - Pipkin, Matthew E
AU  - Pipkin ME
FAU - Djuretic, Ivana M
AU  - Djuretic IM
FAU - Levanon, Ditsa
AU  - Levanon D
FAU - Lotem, Joseph
AU  - Lotem J
FAU - Lichtenheld, Mathias G
AU  - Lichtenheld MG
FAU - Groner, Yoram
AU  - Groner Y
FAU - Rao, Anjana
AU  - Rao A
LA  - eng
GR  - F32 CA126247/CA/NCI NIH HHS/United States
GR  - R01 AI044432/AI/NIAID NIH HHS/United States
GR  - F32 CA126247-01/CA/NCI NIH HHS/United States
GR  - CA42471/CA/NCI NIH HHS/United States
GR  - P30 AI073961/AI/NIAID NIH HHS/United States
GR  - R01 CA042471/CA/NCI NIH HHS/United States
GR  - AI44432/AI/NIAID NIH HHS/United States
GR  - R37 CA042471/CA/NCI NIH HHS/United States
GR  - F32 CA126247-02/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20090112
PL  - United States
TA  - J Exp Med
JT  - The Journal of experimental medicine
JID - 2985109R
RN  - 0 (Core Binding Factor Alpha 3 Subunit)
RN  - 0 (Eomes protein, mouse)
RN  - 0 (Interleukin-2)
RN  - 0 (Receptors, Antigen, T-Cell, alpha-beta)
RN  - 0 (Runx3 protein, mouse)
RN  - 0 (T-Box Domain Proteins)
RN  - 0 (T-box transcription factor TBX21)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 126465-35-8 (Perforin)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 3.4.21.- (Granzymes)
SB  - IM
MH  - Animals
MH  - Blotting, Northern
MH  - Blotting, Western
MH  - CD8-Positive T-Lymphocytes/cytology/drug effects/metabolism
MH  - Cell Differentiation/drug effects/genetics/physiology
MH  - Cells, Cultured
MH  - Core Binding Factor Alpha 3 Subunit/genetics/*physiology
MH  - Cytotoxicity, Immunologic/immunology
MH  - *Gene Expression Regulation
MH  - Granzymes/genetics/metabolism
MH  - Interferon-gamma/metabolism
MH  - Interleukin-2/pharmacology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Models, Biological
MH  - Perforin/genetics/metabolism
MH  - Receptors, Antigen, T-Cell, alpha-beta/genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - T-Box Domain Proteins/genetics/metabolism/*physiology
MH  - T-Lymphocytes, Cytotoxic/cytology/drug effects/*metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
PMC - PMC2626671
EDAT- 2009/01/14 09:00
MHDA- 2009/02/24 09:00
CRDT- 2009/01/14 09:00
PHST- 2009/01/14 09:00 [entrez]
PHST- 2009/01/14 09:00 [pubmed]
PHST- 2009/02/24 09:00 [medline]
AID - jem.20081242 [pii]
AID - 10.1084/jem.20081242 [doi]
PST - ppublish
SO  - J Exp Med. 2009 Jan 16;206(1):51-9. doi: 10.1084/jem.20081242. Epub 2009 Jan 12.