ANTIGEN COMPARTMENTATION AND T-HELPER CELL TOLERANCE INDUCTION

The process of antigen recognition depends in part on the amount of pe ptide antigen available and the affinity of the T cell receptor for a particular peptide-major histocompatibility complex (MHC) molecule com plex. The availability of self antigen is limited by antigen processin g, which is compartmentalized such that peptide antigens presented by MHC class I molecules originate in the cytoplasm, whereas peptide anti gens presented by MHC class II molecules are acquired from the endocyt ic pathway. This segregation of the antigen-processing pathways may li mit the diversity of antigens that influence the development and selec tion of, e.g., CD4-positive, MHC class II-specific T cells. Selection in this case might involve only a subset of self-encoded proteins, spe cifcally those that are plasma membrane bound or secreted. To study th ese aspects of immune development, we engineered pigeon cytochrome c f or expression in transgenic mice in two forms: one in which it was exp ressed as a type IL plasma membrane protein, and a second in which it was targeted to the mitochondria after cytoplasmic synthesis. Experime nts with these mice clearly show that tolerance is induced in the thym us, irrespective of antigen compartmentation. Using radiation bone mar row chimeras, we further show that cytoplasmic/mitochondrial antigen g ains access to the MHC class II pathway by direct presentation. As a r esult of studying the anatomy of the thymus, we show that the amount o f antigen and the affinity of the TCR affect the location and time poi nt of thymocytes undergoing apoptosis.