Intestinal intraepithelial T lymphocytes (IEL) are a significant component of the epithelial layer of the intestine. While they have a unique phenotype and behavior when compared to other T-cell populations, the function of these cells, and the numerous T-cells found in the subepithelial lamina propria tissue, is not known. It has been proposed that these T lymphocytes could play a role in the specific effectors responses to pathogens, in the maintenance of the epithelial layer, or in the induction of oral tolerance. There is evidence, suggesting that some subsets of these T-cells differentiate via an extrathymic pathway that may be centered within the intestine. The studies proposed in this application are intended to elucidate some aspects of the development and selection of these unique intestinal lymphocyte population in the mouse, focusing upon the TCR alpha beta+ population, which is the predominant population in humans. As IEL and LPL are difficult to expand and culture in vitro, the investigator will take full advantage of the powerful tools of transgenic and gene deficient mice to reach her goals. She will study the requirement for MHC molecules in the selection of IEL and LPL. She will attempt to identify the MHC class I molecules involved in the development of the TCR alpha beta+ CD8+ IEL present in TAP1 deficient mice. She intends to determine if extrathymic IEL and LPL are selected within the intestine, by analyzing transgenic mice in which class I or class II molecule expression is confined to this tissue. Using well defined TCR transgenic mouse models, she will identify the phenotype of T-cells selected by the extrathymic pathway. Furthermore, she will determine if IEL and LPL are likely to be subject to a true selection process that depends upon TCR avidity. This TCR transgenic system also will enable her to study the possible negative selection of IEL as well. In summary, the proposed experiments are intended to provide insight into the developmental pathway of intestinal T-cells. This knowledge will be crucial in understanding the physiologic importance of this distinct T-cell population. As intestinal T-cells have possible roles in controlling intestinal inflammation and preventing inflammatory bowel disease, in the induction of oral tolerance, and in the surveillance for cancerous epithelial cells, the results from these studies are likely to have important ramifications for understanding both normal homeostasis and pathological conditions of the intestinal mucosa.
| Elewaut, Dirk; Shaikh, Raziya B; Hammond, Kirsten J L et al. (2003) NIK-dependent RelB activation defines a unique signaling pathway for the development of V alpha 14i NKT cells. J Exp Med 197:1623-33 |
| Shaikh, R B; Santee, S; Granger, S W et al. (2001) Constitutive expression of LIGHT on T cells leads to lymphocyte activation, inflammation, and tissue destruction. J Immunol 167:6330-7 |
