Persistent antigenic stimulation alters the transcriptionprogram in T cells, resulting in antigen-specific tolerance

Abstract

Repetitive antigen stimulation induces peripheral T cell tolerance in vivo. It is notknown, however, whether multiple stimulations merely suppress T cell activation or,alternatively, change the transcriptional program to a distinct, tolerant state. In thisstudy, we have discovered that STAT3 and STAT5 were activated in response to antigenstimulation in vivo, in marked contrast to the suppression of AP-1, NF-jB and NFAT. Inaddition, a number of transcription factors were induced in tolerant T cells followingantigen challenge in vivo, including T-bet, Irf-1 and Egr-2. The altered transcriptionprogram in tolerant cells associates closely with the suppression of cell cycle progressionand IL-2 production, as well as with the induction of IL-10. Studies of T-bet and Egr-2show that the function of T-bet in peptide treatment-induced regulatory T cells is notassociated with Th1 differentiation, but correlates with the suppression of IL-2, whereasexpression 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 differenttranscription factors for T cell activation and/or tolerance during antigen-induced T cellresponses. Persistent antigen stimulation can induce T cell tolerance by changing thebalance of transcription factors.