Publications (91) View all
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Article: Apoptosis is an innate defense function of macrophages against Mycobacterium tuberculosis.
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ABSTRACT: Two different forms of death are commonly observed when Mycobacterium tuberculosis (Mtb)-infected macrophages die: (i) necrosis, a death modality defined by cell lysis and (ii) apoptosis, a form of death that maintains an intact plasma membrane. Necrosis is a mechanism used by bacteria to exit the macrophage, evade host defenses, and spread. In contrast, apoptosis of infected macrophages is associated with diminished pathogen viability. Apoptosis occurs when tumor necrosis factor activates the extrinsic death domain pathway, leading to caspase-8 activation. In addition, mitochondrial outer membrane permeabilization leading to activation of the intrinsic apoptotic pathway is required. Both pathways lead to caspase-3 activation, which results in apoptosis. We have recently demonstrated that during mycobacterial infection, cell death is regulated by the eicosanoids, prostaglandin E(2) (proapoptotic) and lipoxin (LX)A(4) (pronecrotic). Although PGE(2) protects against necrosis, virulent Mtb induces LXA(4) and inhibits PGE(2) production. Under such conditions, mitochondrial inner membrane damage leads to macrophage necrosis. Thus, virulent Mtb subverts eicosanoid regulation of cell death to foil innate defense mechanisms of the macrophage.Mucosal Immunology 02/2011; 4(3):279-87. · 6.96 Impact Factor -
Article: Meeting Report: NIH Workshop on the Tuberculosis Immune Epitope Database.
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ABSTRACT: The Immune Epitope Database (IEDB), an online resource available at http://immuneepitope.org/, contains data on T cell and B cells epitopes of multiple pathogens, including M. tuberculosis. A workshop held in June, 2007 reviewed the existing database, discussed the utility of reference sets of epitopes, and identified knowledge gaps pertaining to epitopes and immune responses in tuberculosis.Tuberculosis 08/2008; 88(4):366-70. · 3.47 Impact Factor -
Article: CD1-restricted T cells in host defense to infectious diseases.
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ABSTRACT: CD1 has been clearly shown to function as a microbial recognition system for activation of T cell responses, but its importance for mammalian protective responses against infections is still uncertain. The function of the group 1 CD1 isoforms, including human CD1a, CDlb, and CDLc, seems closely linked to adaptive immunity. These CD1 molecules control the responses of T cells that are highly specific for particular lipid antigens, the best known of which are abundantly expressed by pathogenic mycobacteria such as Mycobacterium tuberculosis and Mycobacterium leprae. Studies done mainly on human circulating T cells ex vivo support a significant role for group I CD1-restricted T cells in protective immunity to mycobacteria and potentially other pathogens, although supportive data from animal models is currently limited. In contrast, group 2 CD1 molecules, which include human CD1d and its orthologs, have been predominantly associated with the activation of CD1d-restricted NKT cells, which appear to be more appropriately viewed as a facet of the innate immune system. Whereas the recognition of certain self-lipid ligands by CD d-restricted NKT cells is well accepted, the importance of these T cells in mediating adaptive immune recognition of specific microbial lipid antigens remains controversial. Despite continuing uncertainty about the role of CD 1d-restricted NKT cells in natural infections, studies in mouse models demonstrate the potential of these T cells to exert various effects on a wide spectrum of infectious diseases, most likely by serving as a bridge between innate and adaptive immune responses.Current topics in microbiology and immunology 02/2007; 314:215-50. · 4.93 Impact Factor -
Article: Regulation of CD1 function and NK1.1(+) T cell selection and maturation by cathepsin S.
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ABSTRACT: NK1.1(+) T cells develop and function through interactions with cell surface CD1 complexes. In I-A(b) mice lacking the invariant chain (Ii) processing enzyme, cathepsin S, NK1.1(+) T cell selection and function are impaired. In vitro, thymic dendritic cells (DCs) from cathepsin S(-/-) mice exhibit defective presentation of the CD1-restricted antigen, alpha-galactosylceramide (alpha-GalCer). CD1 dysfunction is secondary to defective trafficking of CD1, which colocalizes with Ii fragments and accumulates within endocytic compartments of cathepsin S(-/-) DCs. I-A(k), cathepsin S(-/-) mice do not accumulate class II-associated Ii fragments and accordingly do not display CD1 abnormalities. Thus, function of CD1 is critically linked to processing of Ii, revealing MHC class II haplotype and cathepsin S activity as regulators of NK T cells.Immunity 01/2002; 15(6):909-19. · 21.64 Impact Factor -
Article: Murine CD1d-restricted T cell recognition of cellular lipids.
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ABSTRACT: NKT cells are associated with immunological control of autoimmune disease and cancer and can recognize cell surface mCD1d without addition of exogenous antigens. Cellular antigens presented by mCD1d have not been identified, although NKT cells can recognize a synthetic glycolipid, alpha-GalCer. Here we show that after addition of a lipid extract from a tumor cell line, plate-bound mCD1d molecules stimulated an NKT cell hybridoma. This hybridoma also responded strongly to three purified phospholipids, but failed to recognize alpha-GalCer. Seven of sixteen other mCD1d restricted hybridomas also showed a response to certain purified phospholipids. These findings suggest NKT cells can recognize cellular antigens distinct from alpha-GalCer and identify phospholipids as potential self-antigens presented by mCD1d.Immunity 03/2000; 12(2):211-21. · 21.64 Impact Factor
