BIOSYNTHESIS OF NOVEL CLASS IB MOLECULES

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DESCRIPTION (Adapted from the Investigator's abstract): Classical class I MHC molecules (class Ia) are expressed on all nucleated cells and their roles in antigen presentation to CD8+ T-cells during infection or malignancy are well documented. By contrast, there are a large number of non-classical (class Ib) molecules that typically have a restricted tissue distribution and undefined functions. However, recent studies have implicated certain class Ib molecules in such specialized and diverse functions as resistance to bacterial infection (mouse M3), immune recognition by NK cells (mouse Qa-1 and human HLA-E), embryo implantation (mouse Qa-2 and human HLA-G), gut immunity (mouse TL) and iron homeostasis (mouse and human HFE). Interestingly, certain of these functions involve peptide presentation by class Ib molecules (e.g. M3/formylated peptides and Qa-1/signal peptides) whereas other class Ib molecules (e.g. HFE) appear not to bind peptides. In addition, for many class Ib molecules (e.g. the newly discovered MR1) the peptide binding status is unknown, although their implied structures suggests that they could bind peptides. In spite of the very interesting and diverse biology of the class Ib family, little is known of their biosynthesis due to lack of good reagents. In this application the investigator proposes to introduce a serological epitope into six different class Ib molecules that will specifically identify their respective pre-assembled forms. Using this technique he will have the opportunity to study the interactions of class Ib molecules with their respective assembly partners as well as members of the ER peptide loading complex (tapasin, TAP, calreticulin and Erp57). These studies will determine how disparate chaperone interactions contribute to the unique assembly and tissue expressions displayed by functionally diverse class Ib molecules.