The majority of human intestinal intraepithelial lymphocytes (ilELs) are TCR alpha/beta + CD8+ T-cells. Recent analyses of TCRs expressed by ilELs have shown that a relatively small number of clones are markedly expanded throughout the small or large intestine. This selective clonal expansion suggests that the immune response in the intestinal epithelium is driven by a correspondingly small number of antigens. However, the antigens to which most ilELs are responding and the biological function of these cells in response to antigen recognition are unknown. The investigator's long term goal is to understand the normal function of these cells and how they may contribute to intestinal disease. Further studies to determine whether dominant clones persist in the intestine over a period of years, to identify the ligands they recognize and to determine their effector functions are outlined in this application. A prospective study of dominant ilEL clones will be carried out in patients undergoing resections for colorectal cancer and who return for periodic screening colonoscopies and biopsies.
Aim 1 will determine whether particular dominant ilEL clones persist in these patients, and Aim 2 will address whether these iIELs participate in the response to the tumor.
Aim 3 is to characterize minor ilEL populations. The next two aims are to generate stable ilEL clones (Aim 4) and to identify the proteins involved in epithelial cell recognition by these clones (Aim 5) Finally, Aim 6 addresses the effector functions of ilELs.
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