Expression of MHC class II molecules in different cellular and functional compartments is controlled by differential usage of multiple promoters of the transactivator CIITA

Abstract

The highly complex pattern of expression of major histocompatibility complex class II (MHC‐II) molecules determines both the immune repertoire during development and subsequently the triggering and the control of immune responses. These distinct functions result from cell type‐restricted expression, developmental control and either constitutive or inducible expression of MHC‐II genes. Yet, in these various situations, MHC‐II gene expression is always under the control of a unique transactivator, CIITA. Here we show that the CIITA gene is controlled by several distinct promoters, two of which direct specific constitutive expression in dendritic cells and B lymphocytes respectively, while another mediates γ‐interferon‐induced expression. Thus the cellular, temporal and functional diversity of MHC‐II expression is ultimately controlled by differential activation of different promoters of a single transactivator gene. This provides novel experimental tools to dissect compartment‐specific gain or loss of MHC‐II function in vivo.

Co-occupancy of the interferon regulatory element of the class II transactivator (CIITA) Type IV promoter by interferon regulatory factors 1 and 2

“…Also, CIITA expression may lead to self-antigen presentation by cells a ected in auto-immune diseases. Transcription of the CIITA gene is directed by four tissue-speci®c promoters (Muhlethaler-Mottet et al, 1997). The CIITA Type IV promoter controls the IFN-g induced expression of CIITA in non-professional antigen presenting cells, such as endothelial cells and fibroblasts (Muhlethaler-Mottet et al, 1997).…”

“…Transcription of the CIITA gene is directed by four tissue-speci®c promoters (Muhlethaler-Mottet et al, 1997). The CIITA Type IV promoter controls the IFN-g induced expression of CIITA in non-professional antigen presenting cells, such as endothelial cells and fibroblasts (Muhlethaler-Mottet et al, 1997). Sequence analysis of human and mouse CIITA Type IV promoters identi®ed multiple highly conserved regulatory elements, including a NFkB site, a NF-GMa site, a GAS element, an E-Box, and an IRF-E (Muhlethaler-Mottet et al, 1997).…”

Single nucleotide polymorphisms in MHC2TA, the gene encoding the MHC class II transactivator (CIITA)

“…12 One promoter (p), pI, is responsible for constitutive CIITA expression in dendritic cells while pIII, is responsible for constitutive CIITA expression in B cells. 12,13 A separate promoter, pIV, directs IFN␥-inducible CIITA expression in non-pro- fessional APC, including astrocytes and microglia, 14,15 resident CNS APC that may present antigen to pathogenic CD4 + T cells in central nervous system (CNS) inflammation.…”

“…12 One promoter (p), pI, is responsible for constitutive CIITA expression in dendritic cells while pIII, is responsible for constitutive CIITA expression in B cells. 12,13 A separate promoter, pIV, directs IFN␥-inducible CIITA expression in non-pro- fessional APC, including astrocytes and microglia, 14,15 resident CNS APC that may present antigen to pathogenic CD4 + T cells in central nervous system (CNS) inflammation. In this regard, Rasmussen and colleagues 16 evaluated 111 northern European individuals with either relapsing remitting MS (RRMS) or primary progressive MS (PPMS) and 105 controls and identified one SNP (A→G) at nt 168 ( − 155 relative to transcription initiation) of CIITA pIII in 29% of individuals with MS and 27% of controls.…”

Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes

“…7 Four independent and cell type-specific CIITA promoters (PI-PIV) have been identified in humans. 8 Promoter I (PI) mainly controls CIITA expression in myeloid dendritic cells and macrophages, whereas PIII is active in B cells, activated T cells and plasmacytoid dendritic cells, and the PIV promoter regulates IFNginducible CIITA expression in cells of non-hematopoetic origin and in thymic epithelium. 9 The function of the PII promoter in humans has not yet been fully characterized.…”