Recognition of Lyso-Phospholipids by Human Natural Killer T Lymphocytes

Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
PLoS Biology (Impact Factor: 9.34). 10/2009; 7(10):e1000228. DOI: 10.1371/journal.pbio.1000228
Source: PubMed


Natural killer T (NKT) cells are a subset of T lymphocytes with potent immunoregulatory properties. Recognition of self-antigens presented by CD1d molecules is an important route of NKT cell activation; however, the molecular identity of specific autoantigens that stimulate human NKT cells remains unclear. Here, we have analyzed human NKT cell recognition of CD1d cellular ligands. The most clearly antigenic species was lyso-phosphatidylcholine (LPC). Diacylated phosphatidylcholine and lyso-phosphoglycerols differing in the chemistry of the head group stimulated only weak responses from human NKT cells. However, lyso-sphingomyelin, which shares the phosphocholine head group of LPC, also activated NKT cells. Antigen-presenting cells pulsed with LPC were capable of stimulating increased cytokine responses by NKT cell clones and by freshly isolated peripheral blood lymphocytes. These results demonstrate that human NKT cells recognize cholinated lyso-phospholipids as antigens presented by CD1d. Since these lyso-phospholipids serve as lipid messengers in normal physiological processes and are present at elevated levels during inflammatory responses, these findings point to a novel link between NKT cells and cellular signaling pathways that are associated with human disease pathophysiology.

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Available from: Jenny E Gumperz, Oct 04, 2015
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    • "iNKT cells also recognize other non-microbial antigens, including phosphatidylinositol (PI), phosphatidylglycerol (PG), and phosphatidylethanolamine (PE), although with a weak affinity compared to the strong agonist αGalCer (55). Lysophosphatidylcholine, a lipid generated by lipid-dependent signaling pathways, may also stimulate iNKT cells (56). Other CD1d-presented antigens are the ether-bonded mono-alkyl glycerophosphates that together with the precursors and degradation products of plasmalogens are required for the proper selection and maturation of iNKT cells in the thymus (57). "
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    ABSTRACT: T-cells recognize lipid antigens presented by dedicated antigen-presenting molecules that belong to the CD1 family. This review discusses the structural properties of CD1 molecules, the nature of mycobacterial lipid antigens, and the phenotypic and functional properties of T-cells recognizing mycobacterial lipids. In humans, the five CD1 genes encode structurally similar glycoproteins that recycle in and thus survey different cellular endosomal compartments. The structure of the CD1-lipid-binding pockets, their mode of intracellular recycling and the type of CD1-expressing antigen-presenting cells all contribute to diversify lipid immunogenicity and presentation to T-cells. Mycobacteria produce a large variety of lipids, which form stable complexes with CD1 molecules and stimulate specific T-cells. The structures of antigenic lipids may be greatly different from each other and each lipid may induce unique T-cells capable of discriminating small lipid structural changes. The important functions of some lipid antigens within mycobacterial cells prevent the generation of negative mutants capable of escaping this type of immune response. T-cells specific for lipid antigens are stimulated in tuberculosis and exert protective functions. The mechanisms of antigen recognition, the type of effector functions and the mode of lipid-specific T-cell priming are discussed, emphasizing recent evidence of the roles of lipid-specific T-cells in tuberculosis.
    Frontiers in Immunology 05/2014; 5:219. DOI:10.3389/fimmu.2014.00219
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    • "During viral infections, autoimmune inflammation or cancer iNKT cells are also activated, probably in response to the presentation of endogenous antigens. These include ligands such as peroxisome-derived lipids [30], Lyso-phospholipids [31], and in mice isoglobotrihexosyl ceramide (iGb3) [21]. The presentation of these endogenous ligands can be induced after activation of the innate immune system by TLR-9 engagement in the presence of type-I interferons [32]. "
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    ABSTRACT: Invariant NKT cells are innate lymphocytes with a broad tissue distribution. Here we demonstrate that iNKT cells reside in the central nervous system (CNS) in the absence of inflammation. Their presence in the CNS dramatically augments following inoculation of C57Bl/6 mice with the neurotropic Theiler's murine encephalomyelitis virus (TMEV). At the peak of inflammation the cellular infiltrate comprises 45 000 iNKT cells for 1 250 CD8 T cells specific for the immunodominant TMEV epitope. To study the interaction between these two T cell subsets, we infected both iNKT cell deficient Jα18(-/-) mice and iNKT cell enriched Vα14 transgenic mice with TMEV. The CD8 T cell response readily cleared TMEV infection in the iNKT cell deficient mice. However, in the iNKT cell enriched mice TMEV infection persisted and was associated with significant mortality. This was caused by the inhibition of the CD8 T cell response in the cervical lymph nodes and spleen after T cell priming. Taken together we demonstrate that iNKT cells reside in the CNS in the absence of inflammation and that their enrichment is associated with the inhibition of the anti-viral CD8 T cell response and an augmented mortality during acute encephalomyelitis.
    PLoS ONE 01/2014; 9(1):e87717. DOI:10.1371/journal.pone.0087717 · 3.23 Impact Factor
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    • "In an effort to identify additional endogenous ligands, Cox et al. [59] performed a thorough isolation and characterization analysis of natural ligands eluted from CD1d. Among the eluted ligands, lysophosphotidylcholine (LPC) (and to a lesser extent lysosphingomelin (LSM), Figure 3) was found to stimulate some subsets of iNKT cells [60]. This was particularly interesting because of the reported increased frequency of LPC and LPC-specific T cells found in the plasma of melanoma patients [61]. "
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    ABSTRACT: Natural killer T (NKT) cells are a subset of T cells that recognize glycolipid antigens presented by the CD1d protein. The initial discovery of immunostimulatory glycolipids from a marine sponge and the T cells that respond to the compounds has led to extensive research by chemists and immunologists to understand how glycolipids are recognized, possible responses by NKT cells, and the structural features of glycolipids necessary for stimulatory activity. The presence of this cell type in humans and most mammals suggests that it plays critical roles in antigen recognition and the interface between innate and adaptive immunity. Both endogenous and exogenous natural antigens for NKT cells have been identified, and it is likely that glycolipid antigens remain to be discovered. Multiple series of structurally varied glycolipids have been synthesized and tested for stimulatory activity. The structural features of glycolipids necessary for NKT cell stimulation are moderately well understood, and designed compounds have proven to be much more potent antigens than their natural counterparts. Nevertheless, control over NKT cell responses by designed glycolipids has not been optimized, and further research will be required to fully reveal the therapeutic potential of this cell type.
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