| First Author | Kasler HG | Year | 2012 |
| Journal | EMBO J | Volume | 31 |
| Issue | 23 | Pages | 4453-65 |
| PubMed ID | 23103766 | Mgi Jnum | J:264406 |
| Mgi Id | MGI:6196109 | Doi | 10.1038/emboj.2012.295 |
| Citation | Kasler HG, et al. (2012) Nuclear export of histone deacetylase 7 during thymic selection is required for immune self-tolerance. EMBO J 31(23):4453-65 |
| abstractText | Histone deacetylase 7 (HDAC7) is a T-cell receptor (TCR) signal-dependent regulator of differentiation that is highly expressed in CD4/CD8 double-positive (DP) thymocytes. Here, we examine the effect of blocking TCR-dependent nuclear export of HDAC7 during thymic selection, through expression of a signal-resistant mutant of HDAC7 (HDAC7-DeltaP) in thymocytes. We find that HDAC7-DeltaP transgenic thymocytes exhibit a profound block in negative thymic selection, but can still undergo positive selection, resulting in the escape of autoreactive T cells into the periphery. Gene expression profiling reveals a comprehensive suppression of the negative selection-associated gene expression programme in DP thymocytes, associated with a defect in the activation of MAP kinase pathways by TCR signals. The consequence of this block in vivo is a lethal autoimmune syndrome involving the exocrine pancreas and other abdominal organs. These experiments establish a novel molecular model of autoimmunity and cast new light on the relationship between thymic selection and immune self-tolerance. |
