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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033911-06
Application #
2886825
Study Section
Immunobiology Study Section (IMB)
Program Officer
Ash-Shaheed, Belinda
Project Start
1993-05-01
Project End
2002-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
Sonoda, K H; Faunce, D E; Taniguchi, M et al. (2001) NK T cell-derived IL-10 is essential for the differentiation of antigen-specific T regulatory cells in systemic tolerance. J Immunol 166:42-50
Saubermann, L J; Beck, P; De Jong, Y P et al. (2000) Activation of natural killer T cells by alpha-galactosylceramide in the presence of CD1d provides protection against colitis in mice. Gastroenterology 119:119-28
Rodionov, D G; Nordeng, T W; Pedersen, K et al. (1999) A critical tyrosine residue in the cytoplasmic tail is important for CD1d internalization but not for its basolateral sorting in MDCK cells. J Immunol 162:1488-95
Sonoda, K H; Exley, M; Snapper, S et al. (1999) CD1-reactive natural killer T cells are required for development of systemic tolerance through an immune-privileged site. J Exp Med 190:1215-26
Morales, V M; Christ, A; Watt, S M et al. (1999) Regulation of human intestinal intraepithelial lymphocyte cytolytic function by biliary glycoprotein (CD66a). J Immunol 163:1363-70
Probert, C S; Aitken, E W; Saubermann, L J et al. (1998) T-cell receptor usage in the intestine. Chem Immunol 71:27-39
Exley, M; Porcelli, S; Furman, M et al. (1998) CD161 (NKR-P1A) costimulation of CD1d-dependent activation of human T cells expressing invariant V alpha 24 J alpha Q T cell receptor alpha chains. J Exp Med 188:867-76
Chott, A; Gerdes, D; Spooner, A et al. (1997) Intraepithelial lymphocytes in normal human intestine do not express proteins associated with cytolytic function. Am J Pathol 151:435-42
Probert, C S; Christ, A D; Saubermann, L J et al. (1997) Analysis of human common bile duct-associated T cells: evidence for oligoclonality, T cell clonal persistence, and epithelial cell recognition. J Immunol 158:1941-8
Exley, M; Garcia, J; Balk, S P et al. (1997) Requirements for CD1d recognition by human invariant Valpha24+ CD4-CD8- T cells. J Exp Med 186:109-20

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