Brigham and Women's Hospital
Smith Bldg., Room 552
One Jimmy Fund Way
Boston, MA 02115
Lab Members: 1 graduate student, 8 postdoctoral fellows, 2 junior faculty
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 channels that bind the acyl chain tails of lipid 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 T cells or can secrete Th1, Th2 or Th17 cytokines and mediate host defense against microbial infections or immunopathology. CD1 restricted NKT cells have invariant T cell receptors (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, small GTPase Rab 11, Rab 22a, Arf6 mediated early recycling and AP3 and Arl8 dependent sorting to lysosomes. Once saposins facilitate loading with lipid antigens, CD1 molecules then traffic back to the plasma membrane for recognition by CD1-restricted TCRs.
We recently unraveled the mechanism by which innate NKT cells sense danger and are activated by self-lipid antigens and inflammatory cytokines. This occurs when microbes are recognized by antigen presenting cells via TLRs and other pattern recognition receptors that stimulate secretion of IL-12. Microbial sensing also alters lipid biosynthesis pathways leading to the production of highly potent lipid self-antigens like beta-glucosylceramide that are recognized by NKT TCRs to activate NKT cells. Such innate NKT cell activation mechanisms enable these cells to respond to virtually every microbe, even in the absence of foreign antigen recognition. We are studying the molecular basis for the activation and inactivation (anergy) of NKT cells in host defense and identifying the microbial and self-lipid antigen structures that stimulate them. We have resolved the NKT cell transcriptome and identified a core lymphocyte effector program that is expressed in the basal state in NKT cells and other innate lymphocytes allowing their immediate response, and is also upregulated in adaptive T cells during their maturation from naïve to effector CD4 or CD8 T cells. These studies outline the differences and the similarities between innate and adaptive lymphocytes both in terms of their activation strategies and effector capabilities so that we can understand how immune responses are integrated.
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, also play a key role in regulating inflammation and the proliferative and invasive nature of tissue destruction by fibroblasts in rheumatoid arthritis. In the absence of the synovial cadherin-11, synovial lining formation is attenuated and the inflammatory response in the joint is abated. The synovial lining cells undergo an orchestrated response to inflammation that degrades and invades the cartilage. These studies now provide an underlying concept for rheumatoid arthritis in which the pathologic response is dependent on the reaction of local tissue fibroblasts induced by inflammation to mediate the pathways that result in tissue damage. Moreover, the fibroblasts in tissues like the synovium also function as tissue stromal cells that produce the constitutive and induced chemokines and cytokines necessary to support a chronic inflammatory response. We are defining how fibroblasts in the joints and other tissues regulate inflammation by either supporting or terminating local lymphocyte accumulation. Together, these studies examine the molecular mechanisms by which fibroblasts mediate tissue damage and play an essential and novel role in regulating chronic tissue inflammation.
Brigl M, Tatituri RVV, Watts GFM, Bhowruth V, Leadbetter EA, Barton N, Cohen NR, Hsu FF, Besra GS, and Brenner MB. Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection. J. Exp Med. 2011 Jun 6;208(6):1163-77.
Cohen NR, Tatituri RV, Rivera A, Watts GF, Kim EY, Chiba A, Fuchs BB, Mylonakis E, Besra GS, Levitz SM, Brigl M, Brenner MB. Innate recognition of cell wall β-glucans drives invariant natural killer T cell responses against fungi. Cell Host Microbe. 2011 Nov 17;10 (5):437-50.
Garg S, Sharma M, Ung C, Tuli A, Barral DC, Hava DL, Veerapen N, Besra GS, Hacohen N,and Brenner MB. Lysosomal trafficking, antigen presentation, and microbial killing are controlled by the Arf-like GTPase Arl8b. Immunity. 2011 Aug 26;35(2):182-93.
Lee DM, Kiener HP, Agarwal SK, Noss EH, Watts GFM, Chisaka O, Takeichi M, and Brenner MB. Cadherin-11 in synovial lining formation and pathology in arthritis. Science. 2007; 315:1006-1010.
Chang SK, Noss EH, Chen M, Gu Z, Townsend K, Grenha R, Leon L, Lee SY, Lee DM, Brenner MB. Cadherin-11 regulates fibroblast inflammation. Proc Natl Acad Sci U S A. 2011 May 17;108(20):8402-7.
Last Update: 1/6/2014