Defects in CD8+ Regulatory T Cells in the Lamina Propria of Patients with Inflammatory Bowel Disease

Abstract

Mucosal tolerance is believed to be partly mediated by regulatory T cells. Intestinal epithelial cells (IECs) may play an important role in the generation of such regulatory cells, because they are able to process and present Ag to T cells. Furthermore, we have previously demonstrated that IECs are able to generate regulatory CD8+ T cells in vitro. In the present study, we have analyzed lamina propria (LP) lymphocytes for the presence of such regulatory CD8+ T cells in normal individuals as well as in patients with inflammatory bowel disease (IBD). The results of the present study show that LP CD8+ T cells derived from normal controls possess regulatory activity, whereas both unfractionated LP lymphocytes and purified LP CD4+ T cells do not. The LP CD8+ T cells suppress Ig production by pokeweed mitogen-stimulated PBMCs by 31–80%, in a cell contact-dependent manner. No significant difference in suppression between CD28+ and CD28−CD8+ LP T cells was observed. In contrast to CD8+ T cells from normal LP, CD8+ T cells isolated from LP of IBD patients, did not suppress Ig production by pokeweed mitogen-stimulated PBMC (five of six ulcerative colitis specimens; six of six Crohn’s disease specimens). Furthermore, we demonstrate that the frequency of TCR Vβ5.1-positive CD8+ T cells, which we previously have demonstrated to be regulatory and to be expanded by IECs in vitro, is decreased in IBD LP compared with normal LP. In conclusion, this study demonstrates that CD8+ T cells with regulatory activity are present in the LP of normal healthy individuals, but not in patients with IBD, suggesting that these cells might play an active role in mucosal tolerance.

Autoimmune regulator (AIRE)-deficient CD8+CD28lowregulatory T lymphocytes fail to control experimental colitis

“…Human CD8 + T cells from healthy colon biopsies have in vitro suppressive activity. In contrast, CD8 + T cells from colon biopsies affected with IBD lack such in vitro suppressive activity (36). These results therefore suggest an important role for defective CD8 + Treg function in human IBD and may explain the difference between the effects of human and mouse AIRE deficiency on chronic intestinal inflammation.…”

“…Human CD8 + T cells from healthy colon biopsies have in vitro suppressive activity. In contrast, CD8 + T cells from colon biopsies affected with inflammatory bowel disease (IBD) lack such in vitro suppressive activity (36). In mice, CD8 + cells play a crucial role in the induction of intestinal tolerance to orally administered antigens (37).…”

Generation and Regulation of CD8+ Regulatory T Cells

“…CD8-deficient mice were also more susceptible to relapse of autoimmune arthritis after immunization with self antigens (10), suggesting that regulatory activity of CD8 + T cells might reside in the CD8 + memory pool. CD8 + Treg have also been implicated in the regulation of human autoimmune diseases, including inflammatory bowl disease and MS (11,12).…”

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 .…”