Helix-loop-helix proteins regulate pre-TCR and TCR signaling through modulation of Rel/NF-kappaB activities.
E2A and HEB are basic helix-loop-helix transcription factors essential for T cell development. Complete inhibition of their activities through transgenic overexpression of their inhibitors Id1 and Tal1 leads to a dramatic loss of thymocytes. Here, we suggest that bHLH proteins play important roles in establishing thresholds for pre-TCR and TCR signaling. Inhibition of their function allows double-negative cells to differentiate without a functional pre-TCR, while anti-CD3 stimulation downregulates bHLH activities. We also find that the transcription factor NF-kappaB becomes activated in transgenic thymocytes. Further activation of NF-kappaB exacerbates the loss of thymocytes, whereas inhibition of NF-kappaB leads to the rescue of double-positive thymocytes. Therefore, we propose that E2A and HEB negatively regulate pre-TCR and TCR signaling and their removal causes hyperactivation and apoptosis of thymocytes.
Kim
Dongsoo
D
Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA.
Xu
Min
M
Nie
Lei
L
Peng
Xiao-Cong
XC
Jimi
Eijiro
E
Voll
Reinhard E
RE
Nguyen
Thuan
T
Ghosh
Sankar
S
Sun
Xiao-Hong
XH
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000502:physiology*; D011498:Protein Precursors / Q000502:physiology*; D020569:Proto-Oncogene Proteins c-rel / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D019076:Transgenes
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D011498:Protein Precursors; D020569:Proto-Oncogene Proteins c-rel; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; C407909:TCF3 protein, human; C489532:Tcf12 protein, mouse; C073366:TCF12 protein, human