Structure

Supine orientation of a murine MHC class I molecule on the membrane bilayer. Mitra, A. K. et al. Curr. Biol. 14, 718–724 (2004)

Previous studies looking at the structure of MHC molecules have used recombinant forms consisting of only the extracellular domains. However, these structures do not take into account interactions with specific lipid microdomains of the plasma membrane. To address this, Luc Teyton and colleagues used electron microscopy to analyse the extracellular domains of the MHC class I molecule H–2Kb tethered to a lipid bilayer by a histidine tag. Surprisingly, the MHC molecule was shown to lie on its side parallel to the membrane, rather than standing up perpendicular to the membrane as is usually depicted. This orientation is maintained by ionic interactions between lipid head groups in the membrane and the length of the MHC protein. As the supine orientation was shown to be optimal for binding of the co-receptor CD8, changes in MHC orientation might be another way to regulate T-cell-receptor signalling.

Signalling

The cell-surface receptor SLAM controls T cell and macrophage functions. Wang, N. et al. J. Exp. Med. 199, 1255–1264 (2004)

In this study, mice deficient for signalling lymphocyte activation molecule (SLAM, also known as CD150) were generated and used to analyse the specific contribution of SLAM to immune responses. SLAM-mediated signalling occurs through SLAM-associated protein (SAP), and SAP-deficient mice have a severe X-linked immunodeficiency. As SAP also mediates signalling through five other SLAM-related receptors, the precise contribution of SLAM to the immunodeficiency was unknown. The SLAM-deficient mice had impaired macrophage responses to lipopolysaccharide and increased susceptibility to infection with Leishmania major, as well as defective TH2-cell responses. This indicates that SLAM functions as a co-receptor for signalling through Toll-like receptor 4 and the T-cell receptor.

Innate Immunity

Nucleic acid is a novel ligand for innate immune pattern recognition collectins surfactant proteins A and D and mannose-binding lectin. Palaniyar, N. et al. J. Biol. Chem. 15 May 2004 (doi: 10.1074/jbc.M403763200)

Collectins, including surfactant protein D (SP-D), are extracellular innate immune proteins known to bind microbial carbohydrate patterns. In this study, SP-D was shown to bind linear plasmid DNA directly, as well as synthetic oligonucleotides, even at high salt concentrations. Whereas this strong interaction was mediated largely by the collagen-like region of SP-D, electron microscopy indicated that the globular regions of the molecule also associated with DNA. Furthermore, because SP-D co-localized with the DNA of apoptotic cells, the authors suggest that SP-D functions as an opsonin, binding the DNA of apoptotic cells to enhance their clearance.

Lymphocyte Migration

Identification of hepoxilin A3 in inflammatory events: a required role in neutrophil migration across intestinal epithelia. Mrsny, R. J. et al. Proc. Natl Acad. Sci. USA 101, 7421–7426 (2004)

The factor(s) involved in promoting the migration of neutrophils across epithelial-cell barrriers at mucosal surfaces has until now remained elusive. In this paper, Mrsny et al. identify a crucial role for hepoxilin A3 (hepA3) in neutrophil recruitment to sites of mucosal inflammation. Using an in vitro model of Salmonella typhimurium infection of human intestinal epithelial cells, hepA3 was shown to be enriched on the apical side of epithelial-cell monolayers after infection. Establishment of a hepA3 gradient across epithelial cells in vitro and in vivo enabled neutrophils to migrate across tight junctions but did not cause degranulation of neutrophils. Furthermore, the presence of inhibitors of hepA3 biosynthesis markedly reduced neutrophil-associated tissue trauma, confirming a key role for hepA3 in neutrophil migration.

Innate Immunity

Mycobacteria inhibit nitric oxide synthase recruitment to phagosomes during macrophage infection. Miller, B. H. et al. Infect. Immun. 72, 2872–2878 (2004)

The effective elimination of intracellular pathogens that infect macrophages requires the activity of bactericidal agents such as nitric oxide (NO). In this report, Miller and colleagues explore the mechanism by which inducible nitric oxide synthase (iNOS) is delivered to phagosomes containing ingested microorganisms. After macrophage infection with Escherichia coli, iNOS localized to phagosomes. This process depends on a functional actin cytoskeleton, as presence of the actin microfilament disrupter cytochalasin D inhibited iNOS co-localization. By contrast, when macrophages were infected with Mycobacterium tuberculosis, iNOS did not co-localize with M. tuberculosis-containing phagosomes. The authors suggest that interfering with iNOS recruitment might allow certain pathogens to evade the antibacterial action of NO.

Antigen Presentation

CD1d function is regulated by microsomal triglyceride transfer protein. Brozovic, S. et al. Nature Med. 10, 535–539 (2004)

The MHC-class-I-like molecule CD1d presents glycolipid antigens to natural killer T (NKT) cells, and this study investigated the role of microsomal triglyceride-transfer protein (MTP) — an endoplasmic-reticulum (ER)-resident lipid-transfer protein — in CD1d function. In hepatocytes lacking MTP, CD1d accumulated in the ER and cell-surface expression was reduced. Consequently, endogenous and exogenous glycolipid antigen presentation was impaired. Similar observations were obtained using an intestinal epithelial-cell line, providing evidence for a general role for MTP in CD1d trafficking and antigen presentation. Because the MTP defect led to resistance to NKT-cell-mediated hepatocyte injury and colitis, the authors suggest that MTP blockade might be of clinical benefit in NKT-cell-mediated immunopathologies.