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

Abstract

Cell surface expression of major histocompatibility complex class II (MHCII) molecules is increased during the maturation of dendritic cells (DCs). This enhances their ability to present antigen and activate naive CD4+ T cells. In contrast to increased cell surface MHCII expression, de novo biosynthesis of MHCII mRNA is turned off during DC maturation. We show here that this is due to a remarkably rapid reduction in the synthesis of class II transactivator (CIITA) mRNA and protein. This reduction in CIITA expression occurs in human monocyte-derived DCs and mouse bone marrow–derived DCs, and is triggered by a variety of different maturation stimuli, including lipopolysaccharide, tumor necrosis factor α, CD40 ligand, interferon α, and infection with Salmonella typhimurium or Sendai virus. It is also observed in vivo in splenic DCs in acute myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalitis. The arrest in CIITA expression is the result of a transcriptional inactivation of the MHC2TA gene. This is mediated by a global repression mechanism implicating histone deacetylation over a large domain spanning the entire MHC2TA regulatory region.

The brain as an immune privileged site: dendritic cells of the central nervous system inhibit T cell activation

“…Our data showing that the inhibitory phenotype is unique to CNS-DC while spleen DC from the same EAE animals are stimulatory (Fig. 2) and mature [15] are supported by the observation that spleen and LN DC from rats with EAE can transfer the disease to unprimed animals [28]. This indicates that this latter DC type used for the transfer is able to process and present autoantigens and to stimulate naive T cells [28].…”

“…CIITA form I is indispensable for constitutive expression of MHC class II molecules in professional antigen-presenting cells (APC) such as DC and macrophages [5,12,14]. Its expression is high in immature DC and is then shut down after induction of maturation (reduction to 50% after X 1 h) [15]. Therefore, we hypothesized that the initiation of CNS autoimmunity was due to the invasion by immature DC.…”

“…Maturing DC have been described to rapidly shut down expression of CIITA form I, which reflects a stop in de novo MHC II synthesis [15]. Further, mature DC upregulate CC-chemokine receptor 7 (CCR7) which allows the ELC/MIP3 g -directed homing to regional LN [19] and they down regulate CCR1 which binds the inflammatory chemokines RANTES and MIP1- § .…”

“…BM-DC were prepared as described [15]. DC were frozen at day 11 of culture in 60% RPMI/40% FCS/20% DMSO at 5×10 6 -10×10 6 cells/ml.…”

A novel CARD containing splice-isoform of CIITA regulates nitric oxide synthesis in dendritic cells

“…1B). Consistent with previous reports (Landmann et al, 2001), we observed a significant reduction in the level of DC-CIITA mRNA upon LPS-induction. Interestingly, the mRNA level of the DC-CASPIC did not change in the presence of LPS, indicating that the DC-CIITA-isoform was not regulated at transcriptional In silico mouse genome database search shows that the intron 1 of the mouse DC-CIITA gene contains exon-intron boundaries that agree with consensus splice donor, and thus divides intron 1 (white box) into three parts.…”