Immunology
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Michael Brenner

Division of Rheumatology, Immunology and Allergy
Department of Medicine
Brigham and Women's Hospital
Smith Building, Room 552
One Jimmy Fund Way
Boston, MA 02115
Tel: 617-525-1000
Fax: 617-525-1001
e-mail: mbrenner@rics.bwh.harvard.edu
6 postdoctoral fellows, 5 junior faculty, 3 graduate students

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 bacteria and parasites or are self-lipids 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 that are cytotoxic or secrete IFN-g mediate host defense against microbial infections. The self-antigen specific CD1 restricted NKT cells are critical both in host defense against infection and play important roles in autoimmunity, asthma, colitis and tumor immunity. Our laboratory is defining the role of CD1 restricted T cells in adaptive and innate immunity. We are studying the biochemical and molecular aspects of antigen delivery and 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. We are studying the activation and inactivation of NKT cells in host defense and identifying their specific antigen structures. Our studies are unfolding how CD1a, b, and 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 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 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 synoviocytes 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 synoviocytes 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 how cadherins regulate cell invasion and inflammation.

Papers & Publications:

  1. Moody DB, Young DC, Cheng T-Y, Rosat J-P, Roura-mir C, OConnor PB, Zajonc DM, Walz A, Miller MJ, Levery SB, Wilson IA, Costello CE, Brenner MB. T cell activation by lipopeptide antigens. Science 2004; 303:527-531.
  2. van den Elzen P, Garg S, León L, Brigl M, Leadbetter EA, Gumperz JE, Dascher CC, Cheng T-Y, Sacks FM, Illarionov PA, Besra GS, Kent SC, Moody DB, Brenner MB. Apolipoprotein-mediated pathways of lipid antigen presentation. Nature 2005; 437:906-910.
  3. Lee DM, Kiener HP, Agarwal SK, Noss EH, Watts GFM, Chisaka O, Takeichi M, Brenner MB. Cadherin-11 in synovial lining formation and pathology in arthritis. Science. 2007; 315:1006-1010.
  4. Brigl M, Bry L, Kent SC, Gumperz JE, Brenner MB. Mechanism of CD1d-restricted natural killer T cell activation during microbial infection. Nature Immunol. 2003; 4:1230-1237.
  5. Vincent MS, Leslie DS, Gumperz JE, Xiong X, Grant EP, Brenner MB. CD1-dependent dendritic cell instruction. Nature Immunol. 2002; 3:1163-1168.