Intestinal epithelial cells from inflammatory bowel disease patients preferentially stimulate CD4+ T cells to proliferate and secrete interferon-γ

Abstract

Previous studies have suggested that intestinal epithelial cells (IECs) have the capacity to function as nonprofessional antigen presenting cells that in the normal state preferentially activate CD8+ T cells. However, under pathological conditions, such as those found in inflammatory bowel disease (IBD), persistent activation of CD4+ T cells is seen. The aim of this study was to determine whether the IBD IECs contribute to CD4+ T cell activation. Freshly isolated human IECs were obtained from surgical specimens of patients with or without IBD and cocultured with autologous or allogeneic peripheral blood T lymphocytes. Cocultures of normal T cells and IECs derived from IBD patients resulted in the preferential activation of CD4+ T cell proliferation that was associated with significant IFN-gamma, but not IL-2, secretion. Cytokine secretion and CD4+ T cell proliferation was inhibited by pretreatment of the IBD IECs with the anti-DR MAb L243. In contrast, normal IECs stimulated the proliferation and cytokine secretion by CD4+ T cells to a significantly lesser degree than IBD IECs. Furthermore, blockade of human leukocyte antigen-DR had a lesser effect in the normal IEC-CD4+ T cell cocultures. We conclude that IECs can contribute to the ongoing CD4+ T cell activation seen in IBD. We suggest that the apparent differences between the secreted levels of IFN-gamma indicate that it may play a dual role in intestinal homeostasis, in which low levels contribute to physiological inflammation whereas higher levels are associated with an uncontrolled inflammatory state.

Curcumin inhibits interferon-γ signaling in colonic epithelial cells

“…Next, we analyzed specific and clinically relevant IFN-␥ target genes. IFN-␥ stimulates expression of MHC class II (MHC-II) genes in colonic epithelial cells, which converts them into nonprofessional APCs that promote proinflammatory CD4 ϩ T cell proliferation in IBD patients (12,19). Therefore, it was of clinical relevance to verify whether curcumin is able to downregulate IFN-␥ stimulated MHC-II gene expression in colonocytes.…”

“…IFN-␥ also primes intestinal epithelial cells (IEC) to express major histocompatibility complex (MHC) class II molecules (11,39) and to serve as nonprofessional antigen-presenting cells (APC). IEC isolated from IBD patients have been shown to coexpress costimulatory molecules (CD58, CD86, B7H) and to potently induce proliferation of CD4 ϩ lymphocytes when cocultured (12).…”

The CD40-CD40L Pathway Contributes to the Proinflammatory Function of Intestinal Epithelial Cells in Inflammatory Bowel Disease

“…In active IBD, IECs were shown to stimulate CD4 ϩ and CD8 ϩ effector T cells. 5,6 Therefore, CD40 might be involved in various proinflammatory functions of IECs in innate and adaptive immune responses. Further studies will have to address this issue.…”

“…IECs are known to be involved in the regulation of mucosal immune responses to luminal antigens. 3,4 They function as antigen presenting cells (APCs) to different subsets of T cells 3,[5][6][7] and moreover play a role in the innate immune response through secretion of a panel of cytokines and chemokines. 8 -11 In this regard IECs substantially contribute to the inflammatory processes in IBD by stimulating effector T cells and the release of interleukin (IL)-1, IL-6, IL-8, or tumor necrosis factor (TNF)-␣.…”

Lloyd F. Mayer, MD: a remembrance

“…[7][8][9][10] He was intrigued by the delicate balance between immune activation and tolerance, and hypothesized that the gut epithelium had an essential role in directing the gut immune state in a dynamic way that was relevant to both health and disease. This was a radical departure from the then-prevailing dogma that the IEC was merely the passive partner or innocent bystander of activated immune processes associated with diseases like IBD.…”