Involvement of Secretory and Endosomal Compartments in Presentation of an Exogenous Self-Glycolipid to Type II NKT Cells

Laboratory of Autoimmunity, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121, USA.
The Journal of Immunology (Impact Factor: 4.92). 04/2008; 180(5):2942-50. DOI: 10.4049/jimmunol.180.5.2942
Source: PubMed


Natural Killer T (NKT) cells recognize both self and foreign lipid Ags presented by CD1 molecules. Although presentation of the marine sponge-derived lipid alphaGalCer to type I NKT cells has been well studied, little is known about self-glycolipid presentation to either type I or type II NKT cells. Here we have investigated presentation of the self-glycolipid sulfatide to a type II NKT cell that specifically recognizes a single species of sulfatide, namely lyso-sulfatide but not other sulfatides containing additional acyl chains. In comparison to other sulfatides or alphaGalCer, lyso-sulfatide binds with lower affinity to CD1d. Although plate-bound CD1d is inefficient in presenting lyso-sulfatide at neutral pH, it is efficiently presented at acidic pH and in the presence of saposin C. The lysosomal trafficking of mCD1d is required for alphaGalCer presentation to type I NKT cells, it is not important for presentation of lyso-sulfatide to type II NKT cells. Consistently, APCs deficient in a lysosomal lipid-transfer protein effectively present lyso-sulfatide. Presentation of lyso-sulfatide is inhibited in the presence of primaquine, concanamycin A, monensin, cycloheximide, and an inhibitor of microsomal triglyceride transfer protein but remains unchanged following treatment with brefeldin A. Wortmannin-mediated inhibition of lipid presentation indicates an important role for the PI-3kinase in mCD1d trafficking. Our data collectively suggest that weak CD1d-binding self-glycolipid ligands such as lyso-sulfatide can be presented via the secretory and endosomal compartments. Thus this study provides important insights into the exogenous self-glycolipid presentation to CD1d-restricted T cells.

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    • "We investigated whether intracellular vesicle transport in the T cell is essential for LFA-1-mediated migration. Primaquine (PQ) is a lysosomotrophic amine that slows recycling by blocking membrane fusion of exocytic vesicles and has been used to assess a requirement for vesicular recycling in various T cell activities (Pathak and Blum, 2000; Reid and Watts, 1990; Roberts et al., 2002; Roy et al., 2008). Following 5 min pre-treatment with PQ, both the random migration and average speed of HSB2 T cells were normal at 40 mM, reduced by 40% at 100 mM and by 70% at 300 mM PQ with no impact on cell viability (Fig. 1A). "
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    ABSTRACT: T lymphocytes make use of their major integrin LFA-1 to migrate on surfaces that express ICAM-1 such as blood vessels and inflamed tissue sites. How the adhesions are turned over in order to supply traction for this migration has not been extensively investigated. By following the fate of biotinylated membrane LFA-1 on T lymphocytes, we show in this study that LFA-1 internalization and re-exposure on the plasma membrane are linked to migration. Previously we demonstrated the GTPase Rap2 to be a regulator of LFA-1-mediated migration. SiRNA knockdown of this GTPase inhibits both LFA-1 internalization and also its ability to be re-exposed, indicating that Rap2 participates in recycling of LFA-1 and influences its complete endocytosis-exocytosis cycle. Confocal microscopy images reveal that the intracellular distribution of Rap2 overlaps with endosomal recycling vesicles. Although the homologous GTPase Rap1 is also found on intracellular vesicles and associated with LFA-1 activation, these two homologous GTPases do not co-localize. Little is known about the conformation of the LFA-1 that is recycled. We show that the extended form of LFA-1 is internalized and in Rap2 siRNA-treated T lymphocytes the trafficking of this LFA-1 conformation is disrupted resulting in its intracellular accumulation. Thus LFA-1-mediated migration of T lymphocytes requires Rap2-expressing vesicles to recycle the extended form of LFA-1 that we have previously found to control migration at the leading edge.
    Biology Open 11/2012; 1(11):1161-8. DOI:10.1242/bio.20122824 · 2.42 Impact Factor
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    • "Thus, CD1d-restricted, type II NKT cells may be a novel target for therapeutic intervention in the metabolic syndrome. Searching for regulatory ligands and novel ways of regulation that include the selective elimination of pathogenic type II NKT cells might permit the control of not only metabolic syndrome but also various diseases related to lipid inflammation mediated by NKT cells [43]. "
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    ABSTRACT: The progression of obesity is accompanied by a chronic inflammatory process that involves both innate and acquired immunity. Natural killer T (NKT) cells recognize lipid antigens and are also distributed in adipose tissue. To examine the involvement of NKT cells in the development of obesity, C57BL/6 mice (wild type; WT), and two NKT-cell-deficient strains, Jα18(-/-) mice that lack the type I subset and CD1d(-/-) mice that lack both the type I and II subsets, were fed a high fat diet (HFD). CD1d(-/-) mice gained the least body weight with the least weight in perigonadal and brown adipose tissue as well as in the liver, compared to WT or Jα18(-/-) mice fed an HFD. Histologically, CD1d(-/-) mice had significantly smaller adipocytes and developed significantly milder hepatosteatosis than WT or Jα18(-/-) mice. The number of NK1.1(+)TCRβ(+) cells in adipose tissue increased when WT mice were fed an HFD and were mostly invariant Vα14Jα18-negative. CD11b(+) macrophages (Mφ) were another major subset of cells in adipose tissue infiltrates, and they were divided into F4/80(high) and F4/80(low) cells. The F4/80(low)-Mφ subset in adipose tissue was increased in CD1d(-/-) mice, and this population likely played an anti-inflammatory role. Glucose intolerance and insulin resistance in CD1d(-/-) mice were not aggravated as in WT or Jα18(-/-) mice fed an HFD, likely due to a lower grade of inflammation and adiposity. Collectively, our findings provide evidence that type II NKT cells initiate inflammation in the liver and adipose tissue and exacerbate the course of obesity that leads to insulin resistance.
    PLoS ONE 02/2012; 7(2):e30568. DOI:10.1371/journal.pone.0030568 · 3.23 Impact Factor
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    • "The sphingolipid α-galactosylceramide (αGalCer) isolated from marine sponges, is the classical CD1d ligand for activating NKT cells [40]. CD1 molecules also bind and present other endogenous (self) glycolipid sulfatides [41-44]. Lysosomal α-galactosidase A is highly effective in degrading endogenous lipid antigens, normally limiting autoreactive NKT cell responses [44]. "
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    ABSTRACT: CD1d is a non-classical major histocompatibility class 1-like molecule which primarily presents either microbial or endogenous glycolipid antigens to T cells involved in innate immunity. Natural killer T (NKT) cells and a subpopulation of γδ T cells expressing the Vγ4 T cell receptor (TCR) recognize CD1d. NKT and Vγ4 T cells function in the innate immune response via rapid activation subsequent to infection and secrete large quantities of cytokines that both help control infection and modulate the developing adaptive immune response. T regulatory cells represent one cell population impacted by both NKT and Vγ4 T cells. This review discusses the evidence that NKT cells promote T regulatory cell activation both through direct interaction of NKT cell and dendritic cells and through NKT cell secretion of large amounts of TGFβ, IL-10 and IL-2. Recent studies have shown that CD1d-restricted Vγ4 T cells, in contrast to NKT cells, selectively kill T regulatory cells through a caspase-dependent mechanism. Vγ4 T cell elimination of the T regulatory cell population allows activation of autoimmune CD8+ effector cells leading to severe cardiac injury in a coxsackievirus B3 (CVB3) myocarditis model in mice. CD1d-restricted immunity can therefore lead to either immunosuppression or autoimmunity depending upon the type of innate effector dominating during the infection.
    Virology Journal 01/2011; 8(1):32. DOI:10.1186/1743-422X-8-32 · 2.18 Impact Factor
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