Autoimmune disorders are common and affect all organ systems. There are strong genetic associations between many human autoimmune diseases and molecules of the major histocompatability complex (MHC). One explanation is that altered thymic selection and antigen presentation by disease-associated MHC alleles allows self-reactive cells to escape negative selection and to expand in the periphery. It follows that understanding these autoimmune disease processes begins by determining the mechanisms of thymic selection and peripheral T cell survival. The broad, long-term objective of these studies is to determine the molecular basis for T cell development and T cell memory.
The specific aims are: (1) determine the characteristics of ligands which will positively select a MHC class II restricted T cell; (2) measure the equilibrium binding kinetics of positively selecting and related ligands to determine the relevant binding parameters; (3) determine the effects of positively selecting ligands on the survival of naive T cells and on T cell memory. A unique system of expression will be utilized to identify altered peptide ligands that will positively select 3.L2tg T cells (specific for Hb(64-76)I-Ek) in vivo. One such ligand has already been identified, demonstrating the utility of this approach. The equilibrium binding kinetics between positively selecting ligands and the 3.L2 TCR will be determined using BIAcore analysis and peptide/MHC tetramers. The effect of positively selecting ligands on the maintenance of naive cells and the survival of memory cells will be determined by adoptive transfer experiments using 3.L2tg T cells and mice expressing a single covale nt peptide/I-Ek complex. Progress in the experimental and therapeutic approach to autoimmune inflammation hinges upon elucidation of the factors which select and maintain the peripheral T cell repertoire.
