Actively Anergic

Science's STKE  11 Dec 2001:
Vol. 2001, Issue 112, pp. tw451
DOI: 10.1126/stke.2001.112.tw451

T cells require two stimuli to be activated. If only the T cell receptor (TCR) is bound in the absence of costimulation or the TCR ligation is suboptimal, then the cells enter a state of anergy, whereby later costimulatory signals cannot trigger T cell activation. Tzachanis et al. identified Tob in a subtractive hybridization screen as a gene specifically upregulated in anergic T cells. Tob was a found to be a nuclear protein, highly expressed in peripheral blood lymphocytes. In cultured T cells, Tob expression was highest in resting or anergic T cells, and its expression was suppressed by stimuli that produced T cell activation. Forced overexpression of Tob inhibited T cell proliferation and cytokine production under conditions in which T cells would normally be activated. Further investigation of the mechanisms underlying this suppression of activation showed that Tob inhibited production of cyclins and cyclin-dependent kinases important for the G1 to S transition and increased the production of the cell-cycle inhibitory protein p27kip1. The mechanism by which cytokine production was inhibited appeared to involve the ability of Tob to interact with the transcriptional regulators Smads, especially Smad 2 and Smad 4. Tob increased the DNA binding capacity of Smad 4 and promoted expression of a Smad-dependent reporter gene. The interaction of Tob and Smads in anergic or unstimulated cells appeared to suppress the production of the cytokine interleukin-2. The authors propose that Tob acts to increase the threshold for T cell activation and that one function of one costimulatory signal is to decrease Tob concentrations, allowing activation to proceed. These results are discussed by Hua and Thompson.

D. Tzachanis, G. J. Freeman, N. Hirano, A. A. F. L. van Puijenbroek, M. W. Delfs, A. Berezovskaya, L. M. Nadier, V. A. Boussiotis, Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nature Immunol. 2, 1174-1182 (2001). [Online Journal]

X. Hua, C. B. Thompson, Quiescent T cells: Actively maintaining inactivity. Nature Immunol. 2, 1097-1098 (2001). [Online Journal]