Modulation of human natural killer T cell ligands on TLR-mediated antigen-presenting cell activation

Salio, Mariolina; Speak, Anneliese O.; Shepherd, Dawn; Polzella, Paolo; Illarionov, Petr A.; Veerapen, Natacha; Besra, Gurdyal S.; Platt, Frances M.; Cerundolo, Vincenzo

doi:10.1073/pnas.0710145104

Cited by 174 publications

(216 citation statements)

References 45 publications

(51 reference statements)

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“…A feature of CD1d-restricted T cells is weak activation triggered by recognition of CD1d molecules loaded with self lipids (16). This basal recognition of self-lipid complexes can be further amplified by innate signals and cytokine-driven signals (17)(18)(19), leading to iNKT cell activation during microbial infections, even upon exposure to pathogens not known to contain iNKT cell antigens (20). To study the importance of prosaposin in controlling iNKT cell autoreactivity to activated human APCs, we silenced prosaposin expression in the myelomonocytic cell line THP-1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…iNKT cell activation in response to APCs infected with microbes depends on CD1d-mediated triggering of the TCR and is further modulated by cytokines, such as IL-12, released by APC in response to pattern-recognition receptor triggering (17). To investigate the contribution of CD1d-self lipids toward TCR-mediated iNKT cell activation in the absence of the confounding cytokine signals, we stained Listeriainfected prosaposin-competent and -deficient THP-1 cells with the soluble iNKT TCR, which we have previously shown to be able to detect up-regulation of CD1d-self lipid complexes at the cell surface of Toll-like receptor (TLR) agonist-matured THP-1 cells (19). We demonstrated that Listeria-infected prosaposindeficient THP-1 cells displayed fewer CD1d-lipid complexes at the cell surface, compared with control THP-1 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Soluble iNKT TCR heterodimers were generated as previously described (19). The biotinylated TCR heterodimers were tetramerized by mixing at a 4:1 molar ratio with Streptavidin PE (Molecular Probes) or PE-Cy7 (eBiosciences).…”

Section: Methodsmentioning

confidence: 99%

“…Full-length human CD1d was cloned in the pHR-SIN lentiviral vector. Lentivirus particles were made as previously described (19) and used to infect THP-1 cells (ATCC). Tail-deleted (TD) human CD1d, lacking the last 10 amino acids, was cloned in the pHR-SIN lentiviral vector using a strategy previously described (30).…”

Section: Methodsmentioning

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%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

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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“…TLR triggering also increases the activation of iNKT cells [70,71]. A recent study elegantly demonstrated that iNKT-cell activation in response to TLR9 stimulation required both synthesis of type I IFN and production of charged GSL by DC [70].…”

Section: Multiple Mechanisms Influencing Lipid Antigen Presentationmentioning

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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Innate Immune Recognition of Nucleic Acids

Bauer

2010

The Chemical Biology of Nucleic Acids

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Modulation of human natural killer T cell ligands on TLR-mediated antigen-presenting cell activation

Cited by 174 publications

References 45 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

Innate Immune Recognition of Nucleic Acids

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