A comparison of the antigen‐presenting capabilities of class II MHC‐expressing human lung epithelial and endothelial cells

Abstract

SUMMARYHuman lung alveolar epithelial cells constitutively express class II major histocompatibility complex ( MHC). Human lung microvascular endothelial and small airway epithelial cells can be induced to express class II MHC by stimulation with the pro-inflammatory cytokine interferonc. The levels of class II MHC on lung epithelial and endothelial cells were comparable to those seen on an Epstein-Barr virus (EBV )-transformed B-cell line. However, the costimulatory molecules B7-1 and B7-2 were not expressed. The ability of the class II MHC expressing human lung parenchymal cells to present alloantigen to CD4+ T lymphocytes was investigated. Freshly isolated human alveolar epithelial cells (type II pneumocytes) and monolayers of interferon-cstimulated small airway epithelial and lung microvascular endothelial cells were co-cultured with allogeneic CD4+ T lymphocytes and proliferation determined by [3H ]thymidine incorporation. A clear diÂerence was observed between eÂects of the epithelial and endothelial cells on CD4+ T-lymphocyte activation. Alveolar and small airway epithelial cells failed to stimulate the proliferation of allogeneic CD4+ T lymphocytes whereas lung microvascular endothelial cells did stimulate proliferation. This diÂerence could not be explained by the levels of class II MHC or the lack of B7-1 and B7-2 solely. Microvascular endothelial cells, and not alveolar or small airway epithelial cells, possess B7-independent costimulatory pathways.

An Epithelial Cell Line That Can Stimulate Alloproliferation of Resting CD4+ T Cells, But Not After IFN-γ Stimulation

“…Indeed, in several studies, T cells exposed to IFN-␥-treated epithelial cells became unresponsive to the same HLA Ags presented by professional APC. For example, Frasca et al (12) and Singer et al (39) showed that kidney epithelial cells could induce nonresponsiveness in peripheral CD4 ϩ T cells, while Cunningham et al (11) described a similar phenomenon using lung epithelial cells and Marelli-Berg et al (13) reported similar findings with a thyroid epithelial cell line. This group also showed that at least one of the mechanisms by which epithelial cells are able to induce nonresponsiveness is via Fas (CD95)-mediated apoptosis.…”

“…There is a broad agreement that HLA class II-positive endothelial cells (5,6,16,28,29), but not epithelial cells (7,(11)(12)(13)(14)30), fibroblasts (31,32), or smooth muscle cells (28,33), cause alloproliferation of resting CD4 ϩ T cells. The advantage of CIITA transfection is that it can cause up-regulation of HLA-class II molecules without the pleiotropic effects of IFN-␥.…”

“…In other studies, CIITA has been transfected into fibroblasts (35) and hepatocytes (36), leading to cell surface expression of HLA-class II determinants and efficient presentation of peptide epitopes to HLA-DR-restricted peptide-specific CD4 ϩ T cell clones. It is, however, not unusual to show proliferation of T cell clones and lines to HLA-DR-expressing epithelial cells (11,12,14). It is likely that cloned T cells acquire different costimulatory requirements after prolonged culture, including independence from B7-mediated signals (13).…”

“…Thus, in contrast to professional APC, allostimulation of resting T cells by endothelial cells depends on interactions between LFA-3 on the endothelial cells and TCR CD2 (17). However, in view of the fact that epithelial cells also express LFA-3 (7,11), this does not explain the contrasting abilities of endothelial cells and epithelial cells to cause T cell activation.…”

“…A number of groups have shown that IFN-␥-treated large vessel endothelial cells cause alloproliferation of resting CD4 ϩ T cells in vitro, allowing them to postulate that constitutively HLA class II-positive endothelial cells cause allostimulation of resting T cells in vivo (4 -6). Similarly, human epithelial cells associated with allografts have been shown to be constitutively positive for HLA-DR in vivo (7)(8)(9)(10) and to up-regulate HLA-DR after IFN-␥ stimulation in vitro (11)(12)(13). However, IFN-␥-stimulated epithelial cells do not induce proliferation of allospecific CD4 ϩ T lymphocytes, and may even induce a state of anergy or nonresponsiveness in vitro (14).…”