Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells

Nat Immunol. 2001 Dec;2(12):1174-82. doi: 10.1038/ni730.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Carrier Proteins / physiology*
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Clonal Anergy*
  • Clone Cells
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation
  • Humans
  • Interleukin-2 / biosynthesis
  • Interleukin-2 / genetics
  • Intracellular Signaling Peptides and Proteins*
  • Jurkat Cells
  • Lymphocyte Activation*
  • Oligonucleotides, Antisense / pharmacology
  • Promoter Regions, Genetic
  • RNA, Messenger / biosynthesis
  • Smad2 Protein
  • Smad4 Protein
  • T-Lymphocytes / immunology*
  • Trans-Activators / metabolism
  • Transcription, Genetic
  • Tumor Suppressor Proteins*


  • Carrier Proteins
  • Cytokines
  • DNA-Binding Proteins
  • Interleukin-2
  • Intracellular Signaling Peptides and Proteins
  • Oligonucleotides, Antisense
  • RNA, Messenger
  • SMAD2 protein, human
  • SMAD4 protein, human
  • Smad2 Protein
  • Smad4 Protein
  • TOB1 protein, human
  • Trans-Activators
  • Tumor Suppressor Proteins