Intraintestinal T Lymphopoiesis / Anti-Pancreatic Autoimmunity in the Diabetic BB Rat
1. Characterization of T lymphocyte Development in the Mouse Intestinal Epithelium
The mouse intestinal epithelium is a primary, thymus-independent site of T lymphopoiesis giving rise to one of the largest collections of T cells (IEL) in the adult organism. Among IEL subsets expressing TCR-alpha-beta some are phenotypically and functionally similar to peripheral, thymus-derived CD4+ and CD8+ T cells. In contrast, other IEL subsets are unique in that they contain high frequencies of autoreactive cells and express on their surface non functional TCR/CD3 complexes in association with the a chain of CD8 alone, or in combination with CD4. There is evidence that the migration of mature IEL expressing TCR-alpha-beta is limited to the lamina propria which would therefore represent the site where gut- and thymus-derived T cells interact.
Our objectives are: i) to determine whether the phenotypically and functionally distinct subsets of TCR-alpha-beta + IEL are the products of different lineages, or alternatively, correspond to successive stages of development along a common pathway; ii) to analyze the effects of luminal antigens on IEL development and selection; iii) to characterize the role of gut-derived T cells.
2. Anti-Pancreatic Autoimmunity in the Spontaneously Diabetic BB Rat
The BB rate spontaneously develops an autoimmune type I, insulin-dependent diabetic syndrome (IDDM) very similar to that observed in humans. Several genes contribute to the development of IDDM in the BB rat. One of these genes, autosomal recessive, is responsible for a severe immunodeficiency which is always associated with the diabetic syndrome. This immunodeficiency is characterized by profound peripheral T lymphopenia and by a macrophage-mediated impairment of most T cell functions.
The objective of our research is to elucidate the pathophysiology of the impaired development of BB rat T cells and to characterize the molecular interactions between BB rat T cells and macrophages which result in the dysfunction of T lymphocytes.