Intestinal intraepithelial lymphocytes (IELs) are a phenotypically distinct T cell population of unknown function. The majority of human intestinal IELs express the alpha-beta T cell antigen receptor (TCR), the CD8 accessory molecule and the CD45RO antigen, suggesting that they are major histocompatibility complex (MHC) class I restricted memory T cells. Recent studies of the TCRalpha and beta chains expressed by these cells have shown marked skewing towards one or several variable region genes in individual donors and revealed the presence of dominant IEL clones. Several lines of evidence suggest that the MHC class I-like CD1 molecules, which are expressed by intestinal epithelial cells, may function as antigen presenting molecules for intestinal IELs. Preliminary evidence indicates that CD1 expression may be modified on abnormal epithelial cells. These modifications include changes in CD1d glycosylation, changes in CD1 association with beta2microglobulin and the induction of CDla, b or c expression. Alternate forms of CD1 are, therefore, potential target antigens for IELs involved in immunosurveillence of the intestinal mucosa and other mucosal surfaces. The long term goal of this work is to determine the normal function of mucosal T cells and determine the role these cells may play in some diseases. The major goals of this proposal are to identify dominant T cell clones in the intestine, determine the origin of these clones and identify their physiological ligands.
The specific aims are: 1) Determine the TCR repertoire and origin of dominant IEL and lamina propria lymphocyte (LPL) clones in the small and large intestine. 2) Determine the structure of the CD1d molecules expressed by normal human intestinal epithelial cells and determine whether distinct forms of CD1 are expressed on abnormal epithelial cells. 3) Determine whether members of the CD1 gene family are the physiological ligands for dominant IEL clones or LPL clones.
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