Regulatory T cells and antigen-specific tolerance.
Foxp3-expressing regulatory T cells (Tregs) have an essential function of preventing autoimmune disease in man and mouse. Foxp3 binds to forkhead motifs of about 1,100 genes and the strength of binding increases upon PMA/ionomycin stimulation. In Foxp3-expressing T-cell hybridomas, Foxp3 promoter binding does not lead to activation or suppression of genes which becomes only visible after T-cell activation. These findings are in line with observations by others that Foxp3 exerts important functions through association with Tcell receptor (TCR)-dependent transcription factors in a DNAbinding complex. Tregs can be generated when developing T cells encounter TCR agonist ligands in the thymus. This pro - cess requires costimulatory signals. In contrast, extra thymic conversion of naive T cells into Tregs is inhibited by costimulation. In fact, DC-derived retinoic acid (RA) helps the conversion process by counteracting the negative impact of costimulation. Since AP-1 is produced after costimulation and appears to interfere with Foxp3-NFAT transcription complexes, it is of interest to note that RA interferes with AP-1-dependent transcription. Thus, RA may interfere with the negative impact of costimulation on Treg conversion by interfering with the generation and/or function of AP-1.
Kretschmer
K
K
Harvard Medical School, Dana-Farber Cancer Institute, Boston, Mass., USA.
Apostolou
I
I
Verginis
P
P
von Boehmer
H
H
D000818:Animals; D002454:Cell Differentiation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D037182:T-Cell Antigen Receptor Specificity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015533:Transcriptional Activation; D014212:Tretinoin / Q000276:immunology / Q000378:metabolism*
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018808:Transcription Factor AP-1; D014212:Tretinoin