Elevated and sustained expression of the transcription factors Egr1 and Egr2 controls NKT lineage differentiation in response to TCR signaling.
Interactions driven by the T cell antigen receptor (TCR) determine the lineage fate of CD4(+)CD8(+) thymocytes, but the molecular mechanisms that induce the lineage-determining transcription factors are unknown. Here we found that TCR-induced transcription factors Egr2 and Egr1 had higher and more-prolonged expression in precursors of the natural killer T (NKT) than in cells of conventional lineages. Chromatin immunoprecipitation followed by deep sequencing showed that Egr2 directly bound and activated the promoter of Zbtb16, which encodes the NKT lineage-specific transcription factor PLZF. Egr2 also bound the promoter of Il2rb, which encodes the interleukin 2 (IL-2) receptor β-chain, and controlled the responsiveness to IL-15, which signals the terminal differentiation of the NKT lineage. Thus, we propose that persistent higher expression of Egr2 specifies the early and late stages of NKT lineage differentiation, providing a discriminating mechanism that enables TCR signaling to 'instruct' a thymic lineage.
Committee on Immunology and The Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois, USA.
Michael P
MP
Seiler
Rebecca
R
Mathew
Megan K
MK
Liszewski
Chauncey J
CJ
Spooner
Chauncey
C
Spooner
Kenneth
K
Barr
Fanyong
F
Meng
Harinder
H
Singh
Albert
A
Bendelac
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction
D051766:Early Growth Response Protein 1; D051767:Early Growth Response Protein 2; C486109:Egr1 protein, mouse; C497327:Egr2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011948:Receptors, Antigen, T-Cell; C513267:Zbtb16 protein, mouse