Article (Scientific journals)
Nuclear export of histone deacetylase 7 during thymic selection is required for immune self-tolerance.
Kasler, Herbert G.; Lim, Hyung W.; Mottet, Denis et al.
2012In EMBO Journal
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Keywords :
autoimmunity; gene regulation; histone deacetylase; T-cell development; thymic selection
Abstract :
[en] 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.
Research center :
Giga-Cancer - ULiège
Disciplines :
Oncology
Biochemistry, biophysics & molecular biology
Author, co-author :
Kasler, Herbert G.
Lim, Hyung W.
Mottet, Denis ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases
Collins, Amy M.
Lee, Intelly S.
Verdin, Eric
Language :
English
Title :
Nuclear export of histone deacetylase 7 during thymic selection is required for immune self-tolerance.
Publication date :
2012
Journal title :
EMBO Journal
ISSN :
0261-4189
eISSN :
1460-2075
Publisher :
Wiley-Blackwell, United States
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Herbert G Kasler, Hyung W Lim, Denis Mottet : These authors contributed equally to this work.
Available on ORBi :
since 21 November 2012

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