Class I molecules of the major histocompatibility complex (MHC) consist of a highly polymorphic heavy chain complexed to beta2, microglobulin (beta2m). Class I molecules are expressed on virtually all cell types. Their sole function is to bind antigens and present them to T cell bearing CD8 molecules (Tcd8+). Tcd8+ play a critical role in eradicating intracellular pathogens and tumors. They are also a significant cause of immunopathology, being involved in organ rejection and autoimmune diseases. There has been rapid progress in understanding the physical nature of the antigen-class I complex and in how antigens are generated and become associated with class I molecules in cells. It is now apparent that antigens derived from a cytosolic pool of proteins are translocated into an exocytic compartment by MHC encoded transporter complex. Once transported from the cytosol, antigens bind to class I molecules and are transported to the cell surface. Continuing our studies on the assembly and trafficking of MHC class I molecules in the past year we: 1) obtained the first direct evidence that peptides associate with class I molecules in an early exocytic compartment, 2) genetically engineered a class I molecule retained in the endoplasmic reticulum (ER) that will provide finer resolution into the identity of the compartment in which antigen association occurs, 3) developed a fluorescent derivative of an antigenic peptide that retains the capacity to bind class I molecules and offers the promise of studying class I assembly and transport in living cells, 4) found that cells differentially internalize from the cell surface two different types of class I molecules, and made preliminary findings that suggest that cell surface class I molecules can be returned to the Golgi complex.
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