The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection

Claudia X Dominguez; Robert A Amezquita; Tianxia Guan; Heather D Marshall; Nikhil S Joshi; Steven H Kleinstein; Susan M Kaech

doi:10.1084/jem.20150186

The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection

J Exp Med. 2015 Nov 16;212(12):2041-56. doi: 10.1084/jem.20150186. Epub 2015 Oct 26.

Authors

Claudia X Dominguez¹, Robert A Amezquita², Tianxia Guan², Heather D Marshall¹, Nikhil S Joshi¹, Steven H Kleinstein³, Susan M Kaech⁴

Affiliations

¹ Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
² Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520 Howard Hughes Medical Institute, Chevy Chase, MD 20815.
³ Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520 Interdepartmental Program in Computational Biology and Bioinformatics, Yale University School of Medicine, New Haven, CT 06520 Department of Pathology, Yale University School of Medicine, New Haven, CT 06520.
⁴ Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520 Howard Hughes Medical Institute, Chevy Chase, MD 20815 susan.kaech@yale.edu.

Abstract

The transcription factor T-bet is critical for cytotoxic T lymphocyte (CTL) differentiation, but it is unclear how it operates in a graded manner in the formation of both terminal effector and memory precursor cells during viral infection. We find that, at high concentrations, T-bet induced expression of Zeb2 mRNA, which then triggered CTLs to adopt terminally differentiated states. ZEB2 and T-bet cooperate to switch on a terminal CTL differentiation program, while simultaneously repressing genes necessary for central memory CTL development. Chromatin immunoprecipitation sequencing showed that a large proportion of these genes were bound by T-bet, and this binding was altered by ZEB2 deficiency. Furthermore, T-bet overexpression could not fully bypass ZEB2 function. Thus, the coordinated actions of T-bet and ZEB2 outline a novel genetic pathway that forces commitment of CTLs to terminal differentiation, thereby restricting their memory cell potential.

Publication types

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

MeSH terms

Animals
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
Cell Differentiation / genetics
Cell Differentiation / immunology*
Cluster Analysis
Flow Cytometry
Homeodomain Proteins / genetics
Homeodomain Proteins / immunology*
Host-Pathogen Interactions / immunology
Lectins, C-Type
Lymphocytic Choriomeningitis / genetics
Lymphocytic Choriomeningitis / immunology*
Lymphocytic Choriomeningitis / virology
Lymphocytic choriomeningitis virus / immunology
Lymphocytic choriomeningitis virus / physiology
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Oligonucleotide Array Sequence Analysis
Protein Binding / immunology
Receptors, Immunologic / immunology
Receptors, Immunologic / metabolism
Repressor Proteins / deficiency
Repressor Proteins / genetics
Repressor Proteins / immunology*
Reverse Transcriptase Polymerase Chain Reaction
T-Box Domain Proteins / genetics
T-Box Domain Proteins / immunology*
T-Box Domain Proteins / metabolism
T-Lymphocytes, Cytotoxic / immunology*
T-Lymphocytes, Cytotoxic / metabolism
Transcriptome / genetics
Transcriptome / immunology
Zinc Finger E-box Binding Homeobox 2

Substances

Homeodomain Proteins
Klrg1 protein, mouse
Lectins, C-Type
Receptors, Immunologic
Repressor Proteins
T-Box Domain Proteins
T-box transcription factor TBX21
ZEB2 protein, mouse
Zinc Finger E-box Binding Homeobox 2

Associated data

GEO/GSE72408

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding