Maturation of Dendritic Cells Is Accompanied by Rapid Transcriptional Silencing of Class II Transactivator (Ciita) Expression

doi:10.1084/jem.194.4.379

Published online 20 August 2001. doi:10.1084/jem.194.4.379

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© The Rockefeller University Press, 0022-1007/2001/8/379/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 4, August 20, 2001 379-392

Original Article

Maturation of Dendritic Cells Is Accompanied by Rapid Transcriptional Silencing of Class II Transactivator (Ciita) Expression

Salomé Landmann^a, Annick Mühlethaler-Mottet^a, Luca Bernasconi^b, Tobias Suter^b, Jean-Marc Waldburger^a, Krzysztof Masternak^a, Jean-François Arrighi^c, Conrad Hauser^c, Adriano Fontana^b, and Walter Reith^a

^a Department of Genetics and Microbiology, University of Geneva Medical School, CMU, 1211 Geneva, Switzerland
^b Section of Clinical Immunology, University Hospital Zürich, 8044 Zürich, Switzerland
^c Division of Immunology and Allergy, Department of Dermatology, University Hospital Geneva, 1211 Geneva, Switzerland
Department of Genetics and Microbiology, University of Geneva Medical School, CMU, 1 rue Michel-Servet, 1211 Geneva, Switzerland.41-22-702-57-0241-22-702-56-66

walter.reith{at}medecine.unige.ch

Cell surface expression of major histocompatibility complexclass II (MHCII) molecules is increased during the maturationof dendritic cells (DCs). This enhances their ability to presentantigen and activate naive CD4⁺ T cells. In contrast to increasedcell surface MHCII expression, de novo biosynthesis of MHCIImRNA is turned off during DC maturation. We show here that thisis due to a remarkably rapid reduction in the synthesis of classII transactivator (CIITA) mRNA and protein. This reduction inCIITA expression occurs in human monocyte-derived DCs and mousebone marrow–derived DCs, and is triggered by a varietyof different maturation stimuli, including lipopolysaccharide,tumor necrosis factor ${alpha}$ , CD40 ligand, interferon ${alpha}$ , and infectionwith Salmonella typhimurium or Sendai virus. It is also observedin vivo in splenic DCs in acute myelin oligodendrocyte glycoproteininduced experimental autoimmune encephalitis. The arrest inCIITA expression is the result of a transcriptional inactivationof the MHC2TA gene. This is mediated by a global repressionmechanism implicating histone deacetylation over a large domainspanning the entire MHC2TA regulatory region.

Key Words: MHC class II • class II transactivator • experimental autoimmune encephalitis • bare lymphocyte syndrome • histone deacetylation

Abbreviations used in this paper: BMDC, bone marrow–derivedDC; CIITA, class II transactivator; DC, dendritic cell; EAE,experimental autoimmune encephalitis; MOG, myelin oligodendrocyteglycoprotein; RPA, RNase protection assay; SeV^M, Sendai virusstrain M; TSA, trichostatin A.

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