Persistent antigenic stimulation alters the transcription program in T cells, resulting in antigen-specific tolerance.
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-kappaB 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.
Anderson
Per O
PO
Institute of Cell and Molecular Science, Barts and London School of Medicine, UK.
Manzo
Barbara A
BA
Sundstedt
Anette
A
Minaee
Sophie
S
Symonds
Alistair
A
Khalid
Sabah
S
Rodriguez-Cabezas
Maria E
ME
Nicolson
Kirsty
K
Li
Suling
S
Wraith
David C
DC
Wang
Ping
P
D000818:Animals; D002453:Cell Cycle / Q000276:immunology; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051767:Early Growth Response Protein 2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D020825:T-Box Domain Proteins; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology*; D014162:Transfection; D000098815:T-bet Transcription Factor
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D018984:Epitopes, T-Lymphocyte; D007376:Interleukin-2; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D050760:Cyclin-Dependent Kinase Inhibitor p27; D012313:RNA