Premium
Nuclear export of histone deacetylase 7 during thymic selection is required for immune self‐tolerance
Author(s) -
Kasler Herbert G,
Lim Hyung W,
Mottet Denis,
Collins Amy M,
Lee Intelly S,
Verdin Eric
Publication year - 2012
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2012.295
Subject(s) - biology , histone deacetylase , immune system , histone , selection (genetic algorithm) , nuclear protein , negative selection , genetics , hdac10 , immune tolerance , hdac11 , histone deacetylase 5 , computational biology , microbiology and biotechnology , gene , transcription factor , genome , artificial intelligence , computer science
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‐ΔP) in thymocytes. We find that HDAC7‐ΔP 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.