Cutting Edge: Nonglycosidic CD1d Lipid Ligands Activate Human and Murine Invariant NKT Cells

Silk, Jonathan D.; Salio, Mariolina; Reddy, Bharat; Shepherd, Dawn; Gileadi, Uzi; Brown, James; Masri, S. Hajar; Polzella, Paolo; Ritter, Gerd; Besra, Gurdyal S.; Jones, E Y; Schmidt, Richard R.; Cerundolo, Vincenzo

doi:10.4049/jimmunol.180.10.6452

Cited by 79 publications

(100 citation statements)

References 25 publications

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“…S2A). Conversely, presentation of α-GalCer, of the nonglycosidic derivative threitol ceramide [ThrCer (22)] and of the glycolipid Gal(α1→2)GalCer (hereafter referred to as GalGalCer), which requires processing of the terminal galactose by α-galactosidase A (23), was severely affected by the lack of prosaposin (Fig. S2A).…”

Section: Resultsmentioning

confidence: 99%

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Saposins modulate human invariant Natural Killer T cells self-reactivity and facilitate lipid exchange with CD1d molecules during antigen presentation

Salio

Ghadbane

Dushek³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Lipid transfer proteins, such as molecules of the saposin family, facilitate extraction of lipids from biological membranes for their loading onto CD1d molecules. Although it has been shown that prosaposin-deficient mice fail to positively select invariant natural killer T (iNKT) cells, it remains unclear whether saposins can facilitate loading of endogenous iNKT cell agonists in the periphery during inflammatory responses. In addition, it is unclear whether saposins, in addition to loading, also promote dissociation of lipids bound to CD1d molecules. To address these questions, we used a combination of cellular assays and demonstrated that saposins influence CD1d-restricted presentation to human iNKT cells not only of exogenous lipids but also of endogenous ligands, such as the self-glycosphingolipid β-glucopyranosylceramide, up-regulated by antigen-presenting cells following bacterial infection. Furthermore, we demonstrated that in human myeloid cells CD1d-loading of endogenous lipids after bacterial infection, but not at steady state, requires trafficking of CD1d molecules through an endo-lysosomal compartment. Finally, using BIAcore assays we demonstrated that lipid-loaded saposin B increases the offrate of lipids bound to CD1d molecules, providing important insights into the mechanisms by which it acts as a "lipid editor," capable of fine-tuning loading and unloading of CD1d molecules. These results have important implications in understanding how to optimize lipid-loading onto antigen-presenting cells, to better harness iNKT cells central role at the interface between innate and adaptive immunity. autoreactivity | inflammation | innate immunity | lipid binding proteins

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Section: Resultsmentioning

confidence: 99%

“…For the experiment described in Fig. 3F, bacterially purified human CD1d was refolded with ThrCer, as previously described (22).…”

Section: Methodsmentioning

confidence: 99%

Saposins modulate human invariant Natural Killer T cells self-reactivity and facilitate lipid exchange with CD1d molecules during antigen presentation

Salio

Ghadbane

Dushek³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Section: Mini-reviewmentioning

confidence: 99%

“…These microbial lipid antigens are synthesized by bacteria extracellularly and become available for binding to CD1d after internalization by APC. Also compounds that contain a sugar alcohol with four carbons, such as synthetic threitolceramide, can behave as agonist ligands [14].Two other GSL, namely disialoganglioside GD3 and sulphatide, can stimulate CD1-restricted T cells. Mice immunized with a GD3-releasing tumour cell line develop a GD3-specific CD1d-restricted response [15].…”

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confidence: 99%

The cellular and biochemical rules of lipid antigen presentation

2009

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The recognition of both protein and lipid antigens follows similar strategies that rely on different molecular mechanisms. APC present lipid antigens exploiting the same mechanisms implicated in lipid translocation, lipoprotein assembly and lipid degradation. An important issue is how the lipid structure contributes to antigenicity. Lipid hydrophobicity influences the modes of internalization by APC, the trafficking through different membrane compartments, the binding to CD1 molecules and the stability of antigenic complexes. Some glycolipids with large hydrophilic parts require processing of the sugar moieties exerted by lysosomal hydrolases. Finally, extraction of lipids from membranes, their solubilization and loading on CD1 molecules are facilitated by the same lysosomal lipid-binding proteins that are also instrumental in lipid catabolism. More recent investigations reveal how lipid-specific immunity is regulated during infections. In this review we describe the main cellular and biochemical rules of lipid antigen presentation and discuss their implications in anti-microbial and autoimmune responses.Key words: Antigen recognition . CD1 . Lipid antigens . TCR IntroductionMembers of the MHC or CD1 families present protein and lipid antigens to T cells, respectively. CD1 molecules are differentially expressed by a variety of cell types including DC, B cells, monocytes, Langerhans cells, stellate hepatic cells, epithelial cells, microglial cells and keratinocytes. In humans, five genes (CD1A, B, C, D and E) encode CD1 proteins. CD1a, CD1b, CD1c and CD1d molecules reach the plasma membrane and are involved in lipid presentation to T cells, whereas CD1e remains intracellular and is involved in lipid processing. Lipid-specific T cells express a variety of TCR heterodimers, with the exception of invariant NKT (iNKT) cells, a CD1d-restricted population that uses a semi-invariant TCR (invariant Va24-Ja18 and variable Vb11 chains in humans, invariant Va14-Ja18 and variable Vb8.2, Vb7 or Vb2 chains in mice).Proteins become antigenic after a series of events starting with partial degradation by the cellular machinery represented by the proteasome or by proteases located in lysosomes (Ly) and endoplasmic reticulum (ER). This immunological function, commonly known as antigen processing, leads to the generation of peptide fragments that are carried to the proximity of MHC molecules with which they form antigenic complexes. A similar scheme applies to the presentation of lipid antigens. Lipids derived from extracellular routes are internalized or alternatively, self-lipid antigens are synthesized within the APC. These lipids are then transported into the cellular compartments where CD1 molecules traffic and after loading onto CD1, form antigenic complexes.The physicochemical properties of lipids and peptides impose the utilization of different strategies by the APC to digest, transport and load each of these classes of molecules. Antigenicity of lipids is achieved with the participation of extracellular and intracellular li...

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“…In fact, DCs, when loaded with antigens, are potential candidates for therapies in different diseases, including cancer (8), infection (9) and autoimmune diseases (10). For example, DCs pulsed with ·-galactosylceramide (·-GalCer), a glyco-sphingolipid originally isolated from a marine sponge, effectively activate natural killer T cells (NKT) and show strong anti-tumor and anti-infection activities (11)(12)(13)(14). Meanwhile, studies in our laboratory have shown that the in vivo delivery of fermented Noni Exudate (fNE), a special preparation of Noni juice, not only effectively render mice resistant to tumor challenge but also eradicate existing tumors (15).…”

Section: Introductionmentioning

confidence: 99%

Fermented Noni Exudate-treated dendritic cells directly stimulate B lymphocyte proliferation and differentiation

Zhang

Li²,

Wong³

et al. 2009

Oncol Rep

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Abstract. Noni juice as a folk medicine has been used for over two thousand years. Recently, some active ingredients of Noni juice have been successfully isolated and intensively studied. Because dendritic cells (DCs) are central regulators both in priming innate and adaptive immune responses and in maintaining self tolerance, in the current study we treated DCs with fermented Noni Exudate (fNE) in order to explore their function in regulating other immune cells. It was shown that fNE-treated DCs stimulate proliferation of splenocytes, among which, B cells are the major responsive cell group. The proliferative response of B cells to fNE-treated DCs is cell contact-dependent, CD40L-independent; and the adhesion feature of DCs was enhanced to form large DC-B conjugation cluster. Moreover, it was demonstrated that fNE-treated DCs promote B cell differentiation and Ig class switching. These results lay a foundation for the further exploration of fNE as a biological response modifier in the immune system.

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Cutting Edge: Nonglycosidic CD1d Lipid Ligands Activate Human and Murine Invariant NKT Cells

Cited by 79 publications

References 25 publications

Saposins modulate human invariant Natural Killer T cells self-reactivity and facilitate lipid exchange with CD1d molecules during antigen presentation

Saposins modulate human invariant Natural Killer T cells self-reactivity and facilitate lipid exchange with CD1d molecules during antigen presentation

The cellular and biochemical rules of lipid antigen presentation

Fermented Noni Exudate-treated dendritic cells directly stimulate B lymphocyte proliferation and differentiation

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