Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium.

Abstract

Conventional major histocompatibility complex (MHC) class I genes encode molecules that present intracellular peptide antigens to T cells. They are ubiquitously expressed and regulated by interferon y. Two highly divergent human MHC class I genes, MICA and MICB, are regulated by promoter heat shock elements similar to those ofHSP70 genes. MICA encodes a cell surface glycoprotein, which is not associated with f82-microglobulin, is conformationally stable independent of conventional class I peptide ligands, and almost exclusively expressed in gastrointestinal epithelium. Thus, this MHC class I molecule may function as an indicator of cell stress and may be recognized by a subset of gut mucosal T cells in an unusual interaction. tant cell lines, as well as in immunohistology stainings. The results show that MICA is a.highly glycosylated membraneanchored cell surface protein that is not associated with ,32mand is conformationally stable in the absence of conventional MHC class I peptide ligands. In accord with previous concepts, the almost exclusive expression of MICA in gastrointestinal epithelium combined with the intriguing transcriptional regulation of the MICA gene by a promoter heat shock element implies that this MHC class I molecule may function as a ligand for a subset of T cells in the intestinal intraepithelial lymphocyte compartment. This putative interaction is probably unrelated to conventional MHC class I antigen presentation and may serve a specialized T-cell immune surveillance function.Major histocompatibility complex (MHC) class I molecules are ubiquitously expressed heterodimers of a class I heavy chain and 132-microglobulin (f32m), which display peptides derived from proteins degraded in the cytosol on the cell surface and thus facilitate the recognition of intracellular antigens by circulating cytotoxic CD8+ T cells with ac3 T-cell receptors (1, 2). Class I related molecules have variously altered functions, including the presentation of lipid and lipoglycan compounds to CD4-8-T cells by human CDlb encoded outside the MHC (3, 4). Moreover, so-called nonclassical MHC class I molecules in the mouse selectively present bacterial peptides (5, 6), are recognized by T cells with y6 T-cell receptors in the absence of detectable bound peptides (7-10), or are mainly expressed in intestinal epithelium where they may interact with a subset of the resident T cells (11,12). Although the precise functions of some of these molecules remain to be defined, they are conceptually appreciated as potential components of a firstline immune defense (13,14). However, functionally corresponding genes and molecules have not been found in other mammals and humans. Conversely, two highly divergent human MHC class I genes closely linked to HLA-B, MICA, and MICB are conserved in most if not all mammals but seem to be missing in the mouse (15,16). These genes are transcribed in epithelial cell lines but not in B cells, T cells, and monocytes and are not induced by interferon y. Their translation products share an exc...

Loss of nonclassical MHC molecules MIC-A/B expression during progression of uveal melanoma

“…The MIC gene transcriptional regulatory sequences contain heat-shock elements similar to those in the human Hsp70 promoter. Since genotoxic chemotherapeutic agents such as alkylating, cytotoxic, antimitotic and antimetabolic substances, activate the Hsp70 promoter (Hunt and Morimoto, 1985;Groh et al, 1996) via binding of HSF-1, thereby inducing gene transcription, similar mechanisms, may explain the induction of MIC-A/B expression by fotemustine (Liu et al, 1996). Though induction of MIC-A/B by chemotherapy and subsequent presence of an NKG2D þ inflammatory infiltrate was only investigated in one patient, our previous studies in cutaneous melanoma demonstrated changes in the inflammatory infiltrates at different tumour stages, which were associated with changes in MIC-A/B expression (Vetter et al, 2002), thus strengthening the relevance of these findings in this one patient.…”

High frequencies of alleles MICA*020 and MICA*027 in Amerindians and evidence of positive selection on exon 3

“…4 MICA was thought to be normally expressed only in the gastrointestinal epithelium, 3 but it is possible that it occurs in every organ, except for the central nervous system. 5 Its expression is stress induced, similar to that of heat-shock protein 70, because of a putative heat-shock element in its 5 0 -untranslated region, 6 and it is commonly observed in tumors. 7,8 It binds to an activating receptor of natural killer (NK) cells, NKG2D, and interacts with gd T cells, NK cells and CD8 ab T cells.…”

“…9,10 Differently from other class I molecules, its expression does not depend on the presence of b2-microglobulin or ATP-binding cassette transporter TAP. 6,11 It may have an important role as a first line of defense in the epithelium signaling stressed cells to intraepithelial lymphocytes, but still much has to be learned about the functions of this gene.…”

Killer Ig-like receptor (KIR) genotype and HLA ligand combinations in ulcerative colitis susceptibility

“…10,11 Both the MIC genes (located on chromosome 6p21.3 12,13 ) and ULBP/RAET1 genes (positioned at 6q25 10 ) encode stress-inducible protein products, upregulated in malignant and virally infected cells and constitutively expressed within the epithelium of the gut. 10,11,14,15 The MIC-restricted Vd1 subset of gd T cells are the predominant lymphocyte present within intestinal epithelium. They require co-stimulation via NKG2D, 8 suggesting that the interaction of NKG2D with its ligands may play a role in shaping the immune response within the gut.…”