Division of Rheumatology, Immunology and AllergyBrigham and Women's Hospital
Department of Medicine
Smith Bldg., Room 552
One Jimmy Fund Way
Boston, MA 02115
Lab Members: 8 postdoctoral fellows, 2 junior faculty, 1 graduate student
Visit my lab page here.
Antigen Presentation to T cells:
Our laboratory showed that the cellular immune system is capable not only of recognizing peptides in the context of MHC, but it is also capable of recognizing lipid antigens in the context of CD1 antigen presenting molecules. CD1 molecules (CD1a, b, c and d) are MHC class I-like proteins that contain hydrophobic antigen pockets that bind the lipid tails of antigens, rather than the side chains and backbones 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 antigens include glycolipids (including sphingolipids, diacylglycerols), lipopeptides and fatty acids) that are found in the cell walls of microbes or are self-lipids antigens in mammalian cells. CD1 restricted T cells include all phenotypic subsets, CD8+, CD4+, double negative T cells and NKT cells that recognize professional APCs including macrophages, dendritic cells and B cells. CD1 restricted T cells can be cytotoxic or secrete Th1, Th2 or Th17 cytokines and mediate host defense against microbial infections or mediate immunopathology. CD1 restricted NKT cells have invariant TCRs and are critical both in host defense against infection and play important roles in autoimmunity, asthma, colitis and tumor immunity. NKT cells are innate lymphocytes that mediate immediate, lifesaving, host defense responses.
We are studying the biochemical and molecular aspects of CD1 trafficking, antigen loading and presentation to T cells. We have defined the intracellular trafficking of CD1 molecules as they survey early endosomal and lysosomal compartments to intersect and bind lipid antigens. These studies have identified clathrin dependent, AP2 mediated internalization, Rab 11, Rab 22a, Arf6 mediated early recycling and AP3 and Arl8 dependent sorting to lysosomes. Once antigen loaded, CD1 molecules then traffic back to the plasma membrane for recognition by CD1-restricted TCRs. We recently built shRNA libraries that are being used to identify new molecules involved in the CD1 antigen presenting pathway.
Besides activation of NKT cells by microbial lipid antigens, we have also defined innate, IL-12 cytokine-driven mechanisms of NKT cell activation that are independent of foreign lipid antigens. Such innate NKT cell activation mechanisms enable NKT cells to respond to virtually every microbe. We are studying the molecular basis for activation and inactivation (anergy) of NKT cells in host defense and identifying the microbial and self-lipid antigen structures that are recognized.
Pathophysiology 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 synovial fibroblasts in rheumatoid arthritis and in mouse models of inflammatory arthritis. In the absence of the synovial cadherin, synovial lining formation is attenuated and the inflammatory response in the joint is abated. The synovial tissue response to inflammation is altered and attachment of the synovial fibroblasts to cartilage is averted. These studies now provide an underlying concept for rheumatoid arthritis in which the pathologic response is dependent on the reaction of synovial fibroblasts induced by inflammation that result in tissue damage. The synovial lining cells undergo an orchestrated response to inflammation that results in damage by attachment to and invasion of the cartilage. This orchestrated response requires the cadherin adhesion molecules that mediate the organization of the synovial lining and its pathological behavior in inflammatory arthritis. We are now determining the molecular mechanism by which cadherins regulate cell invasion and inflammation.
Last Update: 8/9/2013