Journal
EMBO JOURNAL
Volume 31, Issue 23, Pages 4453-4465Publisher
WILEY
DOI: 10.1038/emboj.2012.295
Keywords
autoimmunity; gene regulation; histone deacetylase; T-cell development; thymic selection
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Funding
- NIAID NIH HHS [P30 AI027763] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007618] Funding Source: Medline
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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-Delta P) in thymocytes. We find that HDAC7-DP 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. The EMBO Journal (2012) 31, 4453-4465. doi:10.1038/emboj.2012.295; Published online 26 October 2012
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