Expression of nonclassical class I molecules by intestinal epithelial cells

Abstract

It is well recognized that the nature of the immune response is different in the intestinal tract than in peripheral lymphoid organs. The immunologic tone of the gut-associated lymphoid tissue is one of suppression rather than active immunity, distinguishing pathogens from normal flora. Failure to control mucosal immune responses may lead to inflammatory diseases such as Crohn's disease (CD) and ulcerative colitis (UC) and celiac disease. It has been suggested that this normally immunosuppressed state may relate to unique antigen-presenting cells and unique T-cell populations. The intestinal epithelial cell (IEC) has been proposed to act as a nonprofessional antigen-presenting cell (APC). Previous studies have suggested that antigens presented by IECs result in the activation a CD8(+) regulatory T-cell subset in a nonclassical MHC I molecule restricted manner. We therefore analyzed the expression of nonclassical MHC I molecules by normal IECs and compared this to those expressed by inflammatory bowel disease (IBD) IECs. Normal surface IEC from the colon and, to a much lesser extent, the small bowel express nonclassical MHC I molecules on their surface. In contrast, mRNA is expressed in all intestinal epithelial cells. Surface IEC express CD1d, MICA/B, and HLA-E protein. In contrast, crypt IECs express less or no nonclassical MHC I molecules but do express mRNA for these molecules. Furthermore, the regulation of expression of distinct nonclassical class I molecules is different depending on the molecule analyzed. Interestingly, IECs derived from patients with UC fail to express any nonclassical MHC I molecules (protein and HLA-E mRNA). IECs from CD patients express HLA-E and MICA/B comparable to that seen in normal controls but fail to express CD1d. Thus, in UC there may be a failure to activate any nonclassical MHC I molecule restricted regulatory T cells that may result in unopposed active inflammatory responses. In CD only the CD1d-regulated T cells would be affected.

Small intestinal CD8+TCRγδ+NKG2A+ intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease

“…We could not detect HLA-E expression on any TCRγδ + IEL subset. In addition, HLA-E expression on TCRαβ + IELs could be increased 2- to 3-fold upon addition of rhIFN-γ ( Figure 4C), similar to what has been shown for small intestinal enterocyte-derived cell lines (6,32).…”

Ovarian tumor-associated microRNA-20a decreases natural killer cell cytotoxicity by downregulating MICA/B expression

“…7 However, cancer cells are able to reduce the levels of these surface ligands by inducing their downregulation and/or internalization 8 and by causing them to shed their extracellular domains, thus preventing detection by immune cells. 9,10 Recently, MICA/B mRNA has been detected in normal healthy human tissues 11,12 and in adult and normal embryonic mice. 12 This finding indicates that certain post-transcriptional mechanisms may exist to prevent the translation of these mRNAs in healthy individuals, presumably to avoid autoimmunity.…”

Epithelial: Lamina Propria Lymphocyte Interactions Promote Epithelial Cell Differentiation

“…In the intestine, two major lymphocyte populations exist: the intraepithelial lymphocytes (IEL) which remain associated with the basolateral membrane of the IECs, and the LPL which localize to the subepithelial lamina propria and are in contact with IECs via basolateral projections through the semi-porous basement membrane 1,2 . Previous studies from our lab suggested that IECs function as antigen-presenting cells (APCs) and, as such, can promote regulatory T-cell responses in the mucosa [3][4][5][6][7][8] . In a reverse interaction, studies by Chen et al suggested that IEL could induce IEC differentiation via the production of keratinocyte growth factor (KGF) 9 .…”