Persistent antigenic stimulation alters the transcription program in T cells, resulting in antigen‐specific tolerance

Abstract

Repetitive antigen stimulation induces peripheral T cell tolerance in vivo. It is not known, however, whether multiple stimulations merely suppress T cell activation or, alternatively, change the transcriptional program to a distinct, tolerant state. In this study, we have discovered that STAT3 and STAT5 were activated in response to antigen stimulation in vivo, in marked contrast to the suppression of AP‐1, NF‐κB and NFAT. In addition, a number of transcription factors were induced in tolerant T cells following antigen challenge in vivo, including T‐bet, Irf‐1 and Egr‐2. The altered transcription program in tolerant cells associates closely with the suppression of cell cycle progression and IL‐2 production, as well as with the induction of IL‐10. Studies of T‐bet and Egr‐2 show that the function of T‐bet in peptide treatment‐induced regulatory T cells is not associated with Th1 differentiation, but correlates with the suppression of IL‐2, whereas expression of Egr‐2 led to an up‐regulation of the cell cycle inhibitors p21^cip1 and p27^kip. Our results demonstrate a balanced transcription program regulated by different transcription factors for T cell activation and/or tolerance during antigen‐induced T cell responses. Persistent antigen stimulation can induce T cell tolerance by changing the balance of transcription factors. See accompanying commentary http://www.dx.doi.org/10.1002/eji.200636171