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.


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


  • 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