Reference : Nuclear export of histone deacetylase 7 during thymic selection is required for immun...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Human health sciences : Oncology
http://hdl.handle.net/2268/134505
Nuclear export of histone deacetylase 7 during thymic selection is required for immune self-tolerance.
English
Kasler, Herbert G. [> >]
Lim, Hyung W. [> >]
Mottet, Denis mailto [Université de Liège - ULg > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases >]
Collins, Amy M. [> >]
Lee, Intelly S. [> >]
Verdin, Eric [> >]
2012
EMBO Journal
Yes (verified by ORBi)
International
0261-4189
1460-2075
[en] autoimmunity ; gene regulation ; histone deacetylase ; T-cell development ; thymic selection
[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.
Giga-Cancer
http://hdl.handle.net/2268/134505
Herbert G Kasler, Hyung W Lim, Denis Mottet : These authors contributed equally to this work.

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