Antigen Presentation to T cells.

Our laboratory showed that the cellular immune system is capable of not only recognizing peptides in the context of MHC molecules, but it is also capable of recognizing lipid antigens in the context of CD1 molecules. CD1 molecules are MHC class I-like molecules that contain hydrophobic antigen pockets that bind the lipid tails of antigens, rather than the side chains and backbone of peptides. The genes encoding the CD1a, b, c and d molecules represent a distinct lineage of antigen presenting elements that open T cell recognition to the universe of lipid containing self and foreign antigens. These lipid antigens include glycolipids, including sphingolipids, diacylglycerol, lipopeptides and fatty acids that are found in the cell walls of bacteria and parasites or are self-lipids in mammalian cells.

Our laboratory is defining the role of CD1 restricted T cells in adaptive immunity and innate immunity. We are studying the biochemical and molecular aspects of antigen delivery, loading and T cell activation in human in vitro systems and in mouse models. We have defined the intracellular trafficking of CD1 molecules and demonstrated how they survey endosomal compartments to intersect and bind antigens and how this process occurs in infected APCs. Our studies are unfolding how CD1a, b, c mediate clonally restricted adaptive T cell immunity to microbial lipid antigens and how NKT cells mediate innate immunity that provides immediate defense and shapes the subsequent adaptive immune responses.

Pathophysiology of Rheumatoid Arthritis.

We are studying the immunological basis of inflammatory arthritis. We found that cadherins, important adhesion molecules in tissue morphogenesis during development and in the maintenance of tissue architecture in adults, play a key role in the proliferative and invasive nature of synoviocytes in rheumatoid arthritis. In the absence of synovial cadherin, synovial lining formation is attenuated and the inflammatory response in the joint is abated. These studies now provide an underlying concept for rheumatoid arthritis in which the pathologic response is dependent on the reaction of synoviocytes induced by inflammation that can result in tissue damage. We are now determining how cadherins regulate cell invasion and inflammation.

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Michael B. Brenner, M.D.