Immune epithelial cell interaction in response to gastrointestinal infections

Chronic inflammatory disease in the gastrointestinal tract can develop due to an excess of pathogenic T cells or a relative lack of cells producing anti-inflammatory cytokines. Regulatory T cells (Treg) are one subset of Th cells that suppress the ability of pathogenic T cells to induce disease. Fundamentally, it would be helpful to distinguish pathogenic and T reg as well as understand the factors that select for their development so that disease could be controlled by manipulating the mucosal T cell responses.

We have compared the ability of pathogenic T cells and Treg to modify the integrity of epithelial cells in the context of colitis or gastritis associated with chronic Helicobacter pylori infection. In both cases, pathogenic T cells can express FasL and induce apoptosis in epithelial cells expressing Fas. The Fas/FasL interactions are complemented by inflammatory cytokines and oxidative stress than collaborate in mediating the injury to epithelial cells and the disruption of barrier function.

In contrast, Treg do not express FasL after immune activation and they are able to protect epithelial cells from undergoing apoptosis and changes in barrier function. This is despite the fact that some Th cells with Treg function still produce abundant quantities of inflammatory cytokines including interferon-g and TNF-a. IL-10 appears to be a major factor that protects epithelial cells from the effects of pathogenic T cells.

The selection of Treg is dependent on the education of Th cells in the thymus that recognize antigen presented by class II MHC molecules. However, antigen-presenting cells can attenuate the ability of Treg to control inflammation due to cytokines or the expression of GITR ligand that binds to Treg and activated T cells resulting in a loss of tolerance. The significance of this if found in an animal model of inflammatory bowel disease in which pathogenic T cells can be regulated by Treg that appear to develop and function normally. However in the diseased animal, expression of GITR ligand by adjacent cells impairs Treg function resulting in the onset of chronic disease.

These results suggest that Treg can modulate the damage mediated by pathogenic T cells during chronic inflammation. Strategies for the selection of Treg could include novel approaches to alter Th cell activation as well as targeted disruption of factors that impair Treg development and function.