FoxP3 and Regulatory T Cells
Some regulatory T cells express the Foxp3 transcription factor and such Tregs have an essential function of preventing autoimmune disease in man and mouse. Foxp3 binds to Forkhead motifs of about 1100 genes and the strength of binding increases when Foxp3-expressing T cells are stimulated by PMA and ionomycin. In Foxp3-expressing T cell hybridomas, Foxp3 binding to DNA does not lead to the 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 T cell receptor-dependent transcription factors in a DNA-binding complex.
Tregs can be generated when developing T cells encounter TCR agonist ligands in the thymus. This process does not require TGF-β signaling in the T cells but requires costimulatory signals. In contrast, the conversion of naïve T cells into Tregs in peripheral lymphoid tissue essentially depends on TGF-β and is inhibited by costimulation. In fact retinoic acid, produced by some dendritic cells, helps the conversion process by counteracting the negative impact of costimulation on the conversion process. Since AP-1 is produced after costimulation and appears to interfere with a Foxp3-NFAT transcription complex, it is of interest to note that retinoic acid interferes with AP-1-dependent transcription. Thus, retinoic acid may interfere with the negative impact of costimulation on Treg conversion by interfering with the generation and/or function of AP-1.
Peripherally converted Tregs have a stable Foxp3+ phenotype and in mice can survive for several months in the absence of the antigen that induced their formation. In fact the prospective induction of Tregs can be used to generate antigen-specific tolerance that relies on immunosuppression of neighboring CD4 and CD8 T cells by Foxp3+ Tregs in antigen-draining lymph nodes. The mechanisms of suppression may involve cytokines such as TGF-β and IL-10 but also other mechanisms that involve suppressive purine-metabolites such as adenosine or adenosine-monophosphate.
KeywordsRetinoic Acid Thymic Epithelial Cell Peripheral Lymphoid Tissue Pancreatic Lymph Node Foxp3 Transcription Factor
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