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

During a search for genes that maintain T cell quiescence, we determined th at Tob, a member of an anti-proliferative gene family, was highly expressed in anergic T cell clones. Tob was also expressed in unstimulated periphera l blood T lymphocytes and down-regulated during activation. Forced expressi on 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 costimul ation for maximal proliferation and cytokine secretion. Tob associated with Smad2 and Smad4 and enhanced Smad DNA-binding. The inhibitory effect of To b on interleukin 2 (IL-2) transcription was not mediated by blockade of NFA T, 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 quie scence is an actively maintained phenotype that must be suppressed for T ce ll activation to occur.