The Ets-1 transcription factor is required for complete pre-T cell receptor function and allelic exclusion at the T cell receptor beta locus.
The pre-T cell receptor (TCR) functions as a critical checkpoint during alphabeta T cell development. Signaling through the pre-TCR controls the differentiation of immature CD4(-)CD8(-)CD25(+)CD44(-) [double-negative (DN)3] thymocytes into CD4(+)CD8(+) double-positive (DP) cells through the CD4(-)CD8(-)CD25(-)CD44(-)(DN4) stage. In addition, pre-TCR activity triggers expansion and survival of thymocytes and inhibits TCRbeta gene rearrangement through a process referred to as allelic exclusion. Whereas many proteins involved in the pre-TCR transduction cascade have been identified, little is known about the nuclear factors associated with receptor function. Here, we use gene targeting to inactivate the Ets-1 transcription factor in mice and analyze pre-TCR function in developing Ets-1-deficient (Ets-1(-/-)) thymocytes. We find that inactivation of Ets-1 impairs the development of DN3 into DP thymocytes and induces an elevated rate of cell death in the DN4 subset. This defect appears specific to the alphabeta lineage because gammadelta T cells maturate efficiently. Finally, the percentage of thymocytes coexpressing two different TCRbeta chains is increased in the Ets-1(-/-) background and, in contrast with wild type, forced activation of pre-TCR signaling does not block endogenous TCRbeta gene rearrangement. These data identify Ets-1 as a critical transcription factor for pre-TCR functioning and for allelic exclusion at the TCRbeta locus.
Eyquem
Stéphanie
S
Institut National de la Santé et de la Recherche Médicale Unité 462, Institut Universitaire d'Hématologie, 1 avenue Claude Vellefaux, 75475 Paris Cedex 10, France.
Chemin
Karine
K
Fasseu
Magali
M
Bories
Jean-Christophe
JC
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C494042:Ets1 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014157:Transcription Factors; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)