Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells.
During a search for genes that maintain T cell quiescence, we determined that Tob, a member of an anti-proliferative gene family, was highly expressed in anergic T cell clones. Tob was also expressed in unstimulated peripheral blood T lymphocytes and down-regulated during activation. Forced expression of Tob inhibited T cell proliferation and transcription of cytokines and cyclins. In contrast, suppression of Tob with an antisense oligonucleotide augmented CD3-mediated responses and abrogated the requirement of costimulation for maximal proliferation and cytokine secretion. Tob associated with Smad2 and Smad4 and enhanced Smad DNA-binding. The inhibitory effect of Tob on interleukin 2 (IL-2) transcription was not mediated by blockade of NFAT, AP-1 or NF-kappaB transactivation but by enhancement of Smad binding on the -105 negative regulatory element of the IL-2 promoter. Thus, T cell quiescence is an actively maintained phenotype that must be suppressed for T cell activation to occur.
Tzachanis
D
D
Department of Adult Oncology, Dana-Farber Cancer Institute, Division of Medical Oncology, Harvard Medical School, Boston, MA 02115, USA.
Freeman
G J
GJ
Hirano
N
N
van Puijenbroek
A A
AA
Delfs
M W
MW
Berezovskaya
A
A
Nadler
L M
LM
Boussiotis
V A
VA
D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D017635:Clonal Anergy; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D051899:Smad2 Protein; D051901:Smad4 Protein; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins
D002352:Carrier Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; C497782:SMAD2 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051901:Smad4 Protein; C098669:TOB1 protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins