||Major Histocompatibility Complex (MHC) class I molecules are ligands for antigen receptors of CD8 T cells and Natural Killer cells. A major interest in our laboratory is in the MHC class I Antigen Processing and Presentation Pathway, the cellular pathway by which complexes of peptides and MHC class I molecules are generated and displayed on the cell surface. We have studied specific components of this pathway, including the transporter associated with antigen processing (TAP), tapasin, calreticulin, and ERp57.
TAP transports peptides from the cytosol to the ER for binding to class I MHC molecules, and tapasin is an ER-resident MHC class I-specific assembly factor. Our previous and ongoing work has helped define molecular mechanisms relevant to functions of TAP and tapasin. Human MHC class I genes are highly polymorphic, and polymorphism profoundly impacts the intracellular assembly. Recent genetic studies show that closely related MHC class I allotypes are associated with different rates of progression to AIDS, following HIV infection. Some of our current work is directed at understanding whether the intracellular assembly characteristics of an allotype influence the ability of the allotype to mediate a T or NK cell response.
Calreticulin plays important roles in the folding of MHC class I molecules and plant pattern recognition receptors. We are currently defining fundamental features of the biology of substrate interactions with calreticulin, and their regulation by co-chaperones and nucleotide. Although calreticulin is normally ER-resident, it is found at the cell surface in transformed, dying and stressed cells, where it functions as a pro-phagocytic ("eat-me") signal. Our current studies are focused on understanding roles for calreticulin in the phagocytic uptake of cancer cells and apoptotic cells, and molecular interactions relevant to calreticulin-dependent phagocytosis. We are also studying the functional effects of calreticulin mutations that are found in myeloproliferative neoplasms.