9407222 Goverman This is a Research Planning Grant. The long-term objective is to investigate mechanisms in the immune system of establishing tolerance to self antigens. During the planning period of this award, experiments will be carried out to address one possible mechanism for inducing tolerance to the MBP121-140 epitope (amino acids 121-140 of mouse myelin basic protein, a predominant protein in the myelin sheath which has been used extensively as a model system for antibody production to self antigen). The proposed experiments involve the molecular characterization of the T cell receptors (TCRs) expressed on MBP121-140-specific T cells from both "shiverer" mutant mice, which are unable to express endogenous MBP (where the cells are not tolerized) as well as wild-type mice (where tolerance results in a minor response to these residues). Comparing the repertoires of these two different types of mice will permit the testing of the hypothesis that affinity of the T-cell receptor for its ligand is critical in inducing tolerance to this epitope. In this hypothesis, high affinity TCRs which mature in the presence of antigen become tolerized. The minor response observed in wild-type mice could then arise from a small number of cells that were not tolerized simply because they escaped the stochastic process of interaction with antigen, reflecting "leakiness" of tolerance mechanisms. The model predicts that a repertoire of TCRs would be found in shiverer mice that are not found in non shivering litter mates. All possible MBP121-140-specific TCRs would be present in shiverers because of the lack of ligand to tolerize high affinity receptors. However, only receptors representing low-affinity clones would be found in non-shivering mice that express MBP if the high affinity clones are deleted or unresponsive. These studies will lay the basis for an investigation of the in vivo mechanisms for establishing tolerance to MBP. %%% In its response to foreign p athogens, the immune system must be able to discriminate between foreign and self molecules. The recognition of "foreign" antigens is accomplished by lymphocytes. These cells undergo a developmental program in which a large variety of clones of lymphocytes express antigen receptors on their surfaces with different specificities. During lymphocyte maturation in the thymus, a selection process occurs in which those cells bearing receptors which recognize and bind to self-antigens are either destroyed (negative selection) or somehow induced to be non-reactive toward their antigens (anergy). This process is called tolerance. Without tolerance, the immune system would result in self-destruction of the organism. The goal of this project is to understand the molecular mechanism whereby this self-non self discrimination is achieved, using a well established mouse system. ***
