title: Nuclear export of histone deacetylase 7 during thymic selection is required for immune self-tolerance.
abstract: 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.
authors.affiliation: Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158, USA.
authors.forename: Herbert G
authors.initials: HG
authors.lastname: Kasler
authors.forename: Hyung W
authors.initials: HW
authors.lastname: Lim
authors.forename: Denis
authors.initials: D
authors.lastname: Mottet
authors.forename: Amy M
authors.initials: AM
authors.lastname: Collins
authors.forename: Intelly S
authors.initials: IS
authors.lastname: Lee
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D015551:Autoimmunity; D015704:CD4 Antigens / Q000096:biosynthesis*; D016827:CD8 Antigens / Q000096:biosynthesis*; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism*; D007107:Immune System; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D060168:Thymocytes / Q000166:cytology*; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; C543274:Hdac7 protein, mouse; D006655:Histone Deacetylases