The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection.
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.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
Claudia X
CX
Dominguez
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520 Howard Hughes Medical Institute, Chevy Chase, MD 20815.
Robert A
RA
Amezquita
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520 Howard Hughes Medical Institute, Chevy Chase, MD 20815.
Tianxia
T
Guan
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
Heather D
HD
Marshall
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
Nikhil S
NS
Joshi
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.
Steven H
SH
Kleinstein
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520 Howard Hughes Medical Institute, Chevy Chase, MD 20815 susan.kaech@yale.edu.
Susan M
SM
Kaech
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D016000:Cluster Analysis; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000276:immunology; D037181:Lectins, C-Type; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology / Q000502:physiology; 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 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / 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