T cells in the intestinal mucosa face continual antigenic challenge from the contents of the intestine. Therefore, specific mechanisms of immune regulation must have evolved to prevent uncontrolled immune responsiveness in the gut. In fact, there is evidence that loss of proper immune regulation in the intestine leads to inflammatory bowel disease (IBD). Many T cells in the intestinal mucosa of mice express a homodimer form of CD8a chains instead of an W13 heterodimer. Evidence presented in the Preliminary Results section shows that the TL antigen, a class I molecule which is expressed almost exclusively by intestinal epithelial cells in mice, strongly prefers to bind to CD8cw. By contrast, other class I molecules show preference for binding CD8ab. Our data further suggests that the interaction between CD8aa and TL can inhibit immune reactivity. Our overall hypothesis is that the TL-mediated engagement of CD8aa, separately from the TCR-MHC complex, down regulates TCR-mediated signal transduction and thus prevents chronic stimulation. The experiments outlined are designed to explore the TL-CD8acz interaction.
In aim I, the functional consequences, in terms of T cell proliferation, cytotoxicity and cytokine release, will be analyzed in vitro using TL positive presenting cells.
In aim 2, the consequences of this interaction will be explored in vivo. Several transgenic and gene knock out strains, that differ with regard to their TL-CD8aa interactions, will be analyzed for mucosal T cell number and function.
In aim 3, the biochemical basis for preferential binding of the TL antigen to CD8aa will be characterized.
In aim 4, the membrane proximal signal transduction events altered by CD8 aa engagement will be analyzed. The experiments in this application therefore will characterize a novel regulatory mechanism for mucosal T cells. As regulation of and by intestinal T cells is crucial in controlling intestinal inflammation and preventing IBD, in the induction of oral tolerance, and in the surveillance for cancers of epithelial cells, the results from these studies could have important ramifications for understanding normal homeostasis and treatment of pathological conditions in the intestinal mucosa. Furthermore, in mice and humans, CD8aa can be expressed by activated T cells and NK cells, and in vitro studies show that engaging CD8aa on systemic T cells can be inhibitory. Therefore, the mechanisms outlined here could have implications for cancer and other diseases that extend beyond the mucosa.
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