Helix-loop-helix proteins regulate pre-TCR and TCR signaling through modulation of Rel/NF-κB activities

被引:54
作者
Kim, DS
Xu, M
Nie, L
Peng, XC
Jimi, E
Voll, RE
Nguyen, T
Ghosh, S
Sun, XH
机构
[1] Oklahoma Med Res Fdn, Immunobiol & Canc Program, Oklahoma City, OK 73104 USA
[2] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Mol Biophys & Biochem,Sect Immunobiol, New Haven, CT 06520 USA
关键词
D O I
10.1016/S1074-7613(02)00264-9
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:9 / 21
页数:13
相关论文
共 59 条
[1]   HIGH-LEVELS OF C-REL EXPRESSION ARE ASSOCIATED WITH PROGRAMMED CELL-DEATH IN THE DEVELOPING AVIAN EMBRYO AND IN BONE-MARROW CELLS IN-VITRO [J].
ABBADIE, C ;
KABRUN, N ;
BOUALI, F ;
SMARDOVA, J ;
STEHELIN, D ;
VANDENBUNDER, B ;
ENRIETTO, PJ .
CELL, 1993, 75 (05) :899-912
[2]   Constitutive pre-TCR signaling promotes differentiation through Ca2+ mobilization and activation of NF-κB and NFAT [J].
Aifantis, I ;
Gounari, F ;
Scorrano, L ;
Borowski, C ;
von Boehmer, H .
NATURE IMMUNOLOGY, 2001, 2 (05) :403-409
[3]   Positive and negative selection invoke distinct signaling pathways [J].
AlberolaIla, J ;
Hogquist, KA ;
Swan, KA ;
Bevan, MJ ;
Perlmutter, RM .
JOURNAL OF EXPERIMENTAL MEDICINE, 1996, 184 (01) :9-18
[4]   EVIDENCE FOR A DIFFERENTIAL AVIDITY MODEL OF T-CELL SELECTION IN THE THYMUS [J].
ASHTONRICKARDT, PG ;
BANDEIRA, A ;
DELANEY, JR ;
VANKAER, L ;
PIRCHER, HP ;
ZINKERNAGEL, RM ;
TONEGAWA, S .
CELL, 1994, 76 (04) :651-663
[5]   Thymocyte maturation is regulated by the activity of the helix-loop-helix protein, E47 [J].
Bain, G ;
Quong, MW ;
Soloff, RS ;
Hedrick, SM ;
Murre, C .
JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 190 (11) :1605-1616
[6]   Regulation of the helix-loop-helix proteins, E2A and Id3, by the Ras-ERK MAPK cascade [J].
Bain, G ;
Cravatt, CB ;
Loomans, C ;
Alberola-Ila, J ;
Hedrick, SM ;
Murre, C .
NATURE IMMUNOLOGY, 2001, 2 (02) :165-171
[7]   E2A deficiency leads to abnormalities in alpha beta T-cell development and to rapid development of T-cell lymphomas [J].
Bain, G ;
Enel, I ;
Maandag, ECR ;
teRiele, HPJ ;
Voland, JR ;
Sharp, LL ;
Chun, J ;
Huey, B ;
Pinkel, D ;
Murre, C .
MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (08) :4782-4791
[8]  
Barndt R, 1999, J IMMUNOL, V163, P3331
[9]   Functions of E2A-HEB heterodimers in T-cell development revealed by a dominant negative mutation of HEB [J].
Barndt, RJ ;
Dai, MF ;
Zhuang, Y .
MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (18) :6677-6685
[10]   DOES ACTIVATION OF THE TAL1 GENE OCCUR IN A MAJORITY OF PATIENTS WITH T-CELL ACUTE LYMPHOBLASTIC-LEUKEMIA - A PEDIATRIC-ONCOLOGY-GROUP STUDY [J].
BASH, RO ;
HALL, S ;
TIMMONS, CF ;
CRIST, WM ;
AMYLON, M ;
SMITH, RG ;
BAER, R .
BLOOD, 1995, 86 (02) :666-676