HDAC7 regulates apoptosis in developing thymocytes.
Central immune tolerance is established in the thymus for T cells via a complex selection process that involves interactions between CD4+CD8+ double-positive thymocytes and antigen-presenting cells. Cells that express antigen receptors interacting strongly with self peptide MHC complexes are deleted from the repertoire via activation-induced apoptosis, a process termed negative selection. Cells that express an appropriate signal are positively selected and mature into single positive naïve T cells, either CD4 or CD8 positive. The balance between positive and negative selection is thought to play a critical role in the elimination of self-reactive clones and in the establishment of central immune tolerance. We have recently reported that HDAC7, a class II histone deacetylase, is highly expressed in CD4+CD8+ double positive thymocytes. HDAC7 inhibits Nur77 expression, an orphan receptor involved in antigen-induced cell death and in negative selection. The inhibitory effect of HDAC7 on the Nur77 promoter is mediated via the transcription factor MEF2D. During T cell receptor activation, HDAC7 is exported from the nucleus leading to the derepression of Nur77 expression and the induction of apoptosis. These observations define HDAC7 as a regulator of Nur77 and apoptosis in developing thymocytes and indicate that HDAC7 is likely to play an important role in the control of central immune tolerance.
Verdin
Eric
E
Gladstone Institute of Virology and Immunology, Department of Medicine, University of California, San Francisco, PO Box 419100, San Francisco, CA 94141-9100, USA.
Dequiedt
Frank
F
Kasler
Herb
H
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000502:physiology*; D006657:Histones / Q000502:physiology; D006801:Humans; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013950:Thymus Gland / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D006657:Histones; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578043:MEF2D protein, human; D018006:Myogenic Regulatory Factors; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; C543273:HDAC7 protein, human; D006655:Histone Deacetylases