Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection.
ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in epithelial-mesenchymal transition-dependent tumor metastasis. Although the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is up-regulated by activated T cells, specifically in the KLRG1(hi) effector CD8(+) T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8(+) T cells after primary and secondary infection with a severe impairment in the generation of the KLRG1(hi) effector memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress Il7r and Il2 in CD8(+) T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box sites in the Zeb2 gene and that T-bet and ZEB2 regulate similar gene expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Collectively, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8(+) T cells.
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
Kyla D
KD
Omilusik
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
J Adam
JA
Best
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
Bingfei
B
Yu
Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia VIB Inflammation Research Center, Ghent University, 9052 Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
Steven
S
Goossens
Department of Nephrology and Hypertension, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Alexander
A
Weidemann
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
Jessica V
JV
Nguyen
Laboratory of Molecular Biology (Celgen), Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
Eve
E
Seuntjens
Laboratory of Molecular Biology (Celgen), Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
Agata
A
Stryjewska
Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Christiane
C
Zweier
Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Rahul
R
Roychoudhuri
Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Luca
L
Gattinoni
Department of Pediatrics, Rady Children's Hospital San Diego, University of California, San Diego, La Jolla, CA 92093.
Lynne M
LM
Bird
Department of Perinatology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi 480-0392, Japan.
Yujiro
Y
Higashi
Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555, Japan.
Hisato
H
Kondoh
Laboratory of Molecular Biology (Celgen), Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium Department of Cell Biology, Erasmus MC, 3015 CN Rotterdam, Netherlands.
Danny
D
Huylebroeck
Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
Jody
J
Haigh
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093 agoldrath@ucsd.edu.
Ananda W
AW
Goldrath
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D037181:Lectins, C-Type; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding / Q000276:immunology; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020825:T-Box Domain Proteins / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics / Q000276:immunology; D000074165:Zinc Finger E-box Binding Homeobox 2; D000098815:T-bet Transcription Factor
D018398:Homeodomain Proteins; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2