Molecular Genetic Analysis Of Lymphocyte Function

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Abstract

This project is focused on functional studies of NK receptor and T cell receptor recognition. Our approaches include: 1) the development and characterization of mouse strains transgenic for pathogenic T cell receptors--the animals develop autoimmune gastritis, a model for pernicious anemia; and 2) the development of a general system for identifying ligands to NK and T cell receptors that have physiological function. With respect to the first project, we have cloned and expressed a two different TCR from T cell clones that show specificity for two peptides from the gastric H/K ATPase. One of these clones causes a Th1 type disease, and the other a Th2 disease. The Th2 disease is characterized by eosinophilic and polymorphonuclear leukocyte infiltrates in the gastric mucosa. Transgenic animals expressing the TCR from each of these clones have been produced and have been analyzed. The transgenic derived from the Th1 clone, TXA23, develops a fulminant autoimmune gastritis within 10 days of birth. The transgenic derived from the Th2 clone, TXA51, has a less fulminant disease. This second model offers to provide insight into how inflammatory (Th1) cytokines influence autoimmune disease in a manner distinct from Th2 cytokines. Cells taken from the Th2 diseased animals can be maintained in vitro as Th2 cells, or if stimulated with progressive doses of antigenic peptide presented by dendritic cells, can differentiate into Th1 cells. Detailed studies of the pathophysiology of the disease process are in progress.