E2A and HEB are required to block thymocyte proliferation prior to pre-TCR expression.
Thymocytes undergoing TCRbeta gene rearrangements are maintained in a low or nonproliferating state during early T cell development. This block in cell cycle progression is not released until the expression of a functional pre-TCR, which is composed of a successfully rearranged TCRbeta-chain and the Pre-Talpha-chain. The regulatory molecules responsible for the coordination of these differentiation and proliferation events are currently unknown. E2A and HEB are structurally and functionally related basic helix-loop-helix transcription factors involved in T cell development. To reveal the function of E2A and HEB through the stage of pre-TCR expression and alleviate functional compensation between E2A and HEB, we use a double-conditional knockout model. The simultaneous deletion of E2A and HEB in developing thymocytes leads to a severe developmental block before pre-TCR expression and a dramatic reduction of Pre-Talpha expression. These developmentally arrested thymocytes exhibit increased proliferation in vivo and dramatic expansion ex vivo in response to IL-7 signaling. These results suggest that E2A and HEB are not only critical for T cell differentiation but also necessary to retain developing thymocytes in cell cycle arrest before pre-TCR expression.
Wojciechowski
Jason
J
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Lai
Anne
A
Kondo
Motonari
M
Zhuang
Yuan
Y
D000483:Alleles; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000235:genetics; D019674:Genes, T-Cell Receptor beta / Q000235:genetics; D015851:Interleukin-7 / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics*; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000276:immunology*; D051820:TCF Transcription Factors / Q000235:genetics / Q000502:physiology*; D058125:Transcription Factor 7-Like 1 Protein
D051792:Basic Helix-Loop-Helix Proteins; D015851:Interleukin-7; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; C489532:Tcf12 protein, mouse; C544913:Tcf7l1 protein, mouse