The epithelium lining in the gastrointestinal tract displays a variety of functional properties including its ability to act as a physical barrier to luminal contents, promote ion and water transport, absorb nutrients and function as a regulator of mucosal immune responses. It is this latter property, which has been the focus of the investigator's laboratory. Intestinal epithelial cells (IECs) were first described as participants in mucosal immune responses by virtue of their ability to transport sIgA from the lamina propria to the lumen through the use of secretory component. During the period covering this application a more primary role for IECs in mucosal immunoregulation has been defined; that of nonprofessional antigen presenting cell (APC). During this most recent period they have identified two surface molecules which appear to regulate the activation of a unique population of CD8+ suppressor T cells; a novel CD8 ligand gp180 and the nonclassical class I molecule, CD1d. It is the complex of gp180 and CD1d that activates these cells by virtue of their interaction with CD8 and the TcR respectively. This results in not only the activation of a selected subpopulation of cells but also produces a unique set of intracellular signals. The hypothesis guiding this application is that antigens sampled by IECs from the gut lumen are processed in such a way as to favor the nonclassical class I pathway and that class 1b molecules interact with gp180 to form a complex on IECs that can be recognized by regulatory CD8+ T cells. The distinct components governing this interaction require further characterization. To accomplish this, the aims of this renewal are as follows:
Specific Aim #1. Complete the characterization of the novel CD8 ligand gp180; to define its interactions with nonclassical class I molecules; to characterize the molecular and the post-translational modifications required to allow for interaction of gp180 with both CD8 and nonclassical class I molecules.
Specific Aim #2. To define the nature of the signals transduced by ligation of CD8 by gp180 and CD1d, which promote the activation of suppressor T cells in these co-cultures.
Specific Aim #3. To further characterize the regulation of gp180 expression on intestinal epithelial cells and define a potential role for this molecule on non-IECs.
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