Regulation of MHC Protein Expression in Pancreatic β-Cells by Interferon-γ and Tumor Necrosis Factor-α

Abstract

Isolated human and mouse pancreatic islet cells and the rat insulinoma cell line RIN-m5F were used to examine the ability of recombinant interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) to regulate the expression of the class I and class II major histocompatibility (MHC) surface proteins and mRNA in beta-cells. Each cytokine increased significantly the expression of class I MHC proteins as determined by double indirect immunofluorescence microscopy and flow cytofluorimetric analysis. In the RIN-m5F cells, this increase in surface expressed class I MHC proteins was mirrored by an increase in the level of class I MHC mRNA. The order of potency of the cytokines on class I MHC expression was TNF-alpha plus IFN-gamma greater than or equal to IFN-gamma greater than or equal to TNF-alpha. While IFN-gamma or TNF-alpha alone were without effect, in combination they were found to induce class II MHC proteins on 30-40% of human or murine beta-cells. In contrast, IFN-gamma plus TNF-alpha did not induce detectable class II MHC proteins or mRNA in the RIN-m5F cells. These findings indicate that 1) TNF-alpha, in addition to IFN-gamma, upregulates the expression of beta-cell class I MHC proteins and mRNA, and 2) more than one signal is required for the induction of class II MHC proteins on beta-cells. The ability of IFN-gamma plus TNF-alpha to induce class II MHC proteins on only a fraction of the normal beta-cell population and not on RIN-m5F cells suggests that this response is related to the differentiation state of the beta-cell.

Pancreatic NOD beta cells express MHC class II protein and the frequency of I-Ag7 mRNA-expressing beta cells strongly increases during progression to autoimmune diabetes

“…Indeed, several reports propose that the beta cell itself could be capable of presenting antigens in the context of MHC class II molecules. MHC class II expression on beta cells has been shown to be inducible in vitro by IFN-γ and TNF-α in normal mouse islet beta cells [6,11], on cultured human islets [7] and by IFN-γ alone on beta cells from diabetesprone BB rats [12]. Moreover, beta cells from the pancreas of patients with recent-onset Type-1-diabetes [9,13] as well as from diabetes-prone BB rats [10] express MHC class II molecules.…”

“…This is based on the following observations: (i) induction of MHC class II expression (as well as expression of Fas and TNFR2) comes along with the occurrence of insulitis; (ii) in 9-to 10-weekold NOD/SCID mice, the islets of which are free of any lymphocytic infiltration, beta cells express MHC class II mRNA at the same low frequency as beta cells from insulitis-free islets of NOD mice of 3 weeks of age (excluding the possibility that MHC class II expression is a developmental event); (iii) TNF-α and IFN-γ have been shown to be expressed by infiltrating cells [23]; (iv) these cytokines have been shown to be able to trigger expression of MHC class II on beta cells in vitro [6,11]. In the same way TNFR2 and Fas could be triggered by these cytokines, possibly in concert with IL-1 (also known to be expressed by islet-infiltrating cells early in pathogenesis [23]) in the case of Fas.…”

“…A series of publications also provided evidence that beta cells can be induced to express MHC class II molecules [6,7,8,9,10,11,12,13]. However, since it has been reported that MHC class II molecules in NOD islets are expressed exclusively by CD45+ cells [14], that is, cells of haematopoietic origin, it is generally accepted that NOD beta cells are I-A g7 -negative and therefore cannot directly be recognised by self-reactive CD4+ T cells [15].…”

Cytokines and autoimmunity

“…Both IFN-y and TNF increase class I antigen expression on human ;8 islet cells [44] and on RINm5F cells [45], and by such a mechanism these cytokines may facilitate the development of T cell-mediated cytotoxicity towards islet cells. Furthermore, an association has been found between certain autoimmune diseases and a genetically determined hyperinducibility of class II molecules on target cells which is mediated by IFN-y.…”

Nonimmune thyroid destruction results from transgenic overexpression of an allogeneic major histocompatibility complex class I protein.

“…The direct infection of cultured human pancreatic islet cells by reovirus (9) or of rat thyrocytes by simian virus 40 (3) causes upregulation of MHC class I expression. In endocrine autoimmunity, mononuclear cells infiltrate the target tissue and release cytokines such as gamma interferon and tumor necrosis factor, which may further upregulate MHC class I and induce MHC class II molecules in islet cells (6,(10)(11)(12)33) and thyrocytes (22,24,28,32). The overexpression of MHC class I molecules should thus enhance the immunogenic properties of endocrine cells (8,19).…”