| First Author | Ma J | Year | 2011 |
| Journal | PLoS One | Volume | 6 |
| Issue | 9 | Pages | e24768 |
| PubMed ID | 21935461 | Mgi Jnum | J:177880 |
| Mgi Id | MGI:5296431 | Doi | 10.1371/journal.pone.0024768 |
| Citation | Ma J, et al. (2011) Critical role of TCF-1 in repression of the IL-17 gene. PLoS One 6(9):e24768 |
| abstractText | Overwhelming activation of IL-17, a gene involved in inflammation, leads to exaggerated Th17 responses associated with numerous autoimmune conditions, such as experimental autoimmune encephalomyelitis (EAE). Here we show that TCF-1 is a critical factor to repress IL-17 gene locus by chromatin modifications during T cell development. Deletion of TCF-1 resulted in increased IL-17 gene expression both in thymus and peripheral T cells, which led to enhanced Th17 differentiation. As a result, TCF-1(-/-) mice were susceptible to Th17-dependent EAE induction. Rag1(-/-) mice reconstituted with TCF-1(-/-) T cells were also susceptible to EAE, indicating TCF-1 is intrinsically required to repress IL-17. However, expression of wild-type TCF-1 or dominant negative TCF-1 did not interfere with Th17 differentiation in mature T cells. Furthermore, expression of TCF-1 in TCF-1(-/-) T cells could not restore Th17 differentiation to wild-type levels, indicating that TCF-1 cannot affect IL-17 production at the mature T cell stage. This is also supported by the normal up-regulation or activation in mature TCF-1(-/-) T cells of factors known to regulate Th17 differentiation, including RORgammat and Stat3. We observed hyperacetylation together with trimethylation of Lys-4 at the IL-17 locus in TCF-1(-/-) thymocytes, two epigenetic modifications indicating an open active state of the gene. Such epigenetic modifications were preserved even when TCF-1(-/-) T cells migrated out of thymus. Therefore, TCF-1 mediates an active process to repress IL-17 gene expression via epigenetic modifications during T cell development. This TCF-1-mediated repression of IL-17 is critical for peripheral T cells to generate balanced immune responses. |
