Recognition of Lyso-Phospholipids by Human Natural Killer T Lymphocytes

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The authors note that, due to a printer's error, on page 5054, right column, second paragraph, eighth line, "Within this clade, we estimated the mean age of the split between the ABC bears and the polar bears to be 152 ky, and the mean age for all polar bears as 134 ky, near the end of the Eemian interglacial period and completely in line with the stratigraphically determined age of the Poolepynten subfossil (11)," should instead appear as "Within this clade, we estimated the mean age of the split between the ABC bears and the polar bears to be 152 ky, and the mean age for all polar bears as 134 ky, near the beginning of the Eemian interglacial period and completely in line with the stratigraphically determined age of the Poolepynten subfossil (11)." This error does not affect the conclusions of the article. This error has been corrected online and in print.www.pnas.org/cgi

mentioning

confidence: 99%

Activation state and intracellular trafficking contribute to the repertoire of endogenous glycosphingolipids presented by CD1d

Muindi

Cernadas

Watts

et al. 2010

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“…Actual measurements of mouse CD1d complexes formed in cells first suggested that cellular ligands were dominated by one class of phosphatidylinositol-containing molecule (2), and CD1b was reported to bind PC in a selective way (27). However, subsequent study of mouse and human CD1d detected several types of phospho-and sphingolipid ligands (12)(13)(14), suggesting greater diversity of lipid ligands for CD1d. Using cellular CD1 proteins lacking endosomal targeting motifs and captured under two different conditions that avoid the acid-mediated unloading effects, our comparative lipidomics approach provides evidence for substantial diversity of CD1 ligands for each of the four human CD1 proteins, detecting hundreds of molecular features whose retention times vary greatly.…”

Section: Discussionmentioning

confidence: 99%

“…This expectation is supported by experiments that detect self-diacylglycerols, monoacylglycerols, and sphingolipids eluted from CD1 proteins that have ER retention signals or lack endosomal recycling motifs (2,12,13). Some of these endogenous lipids activate T cells, so are true autoantigens (14). Others are more likely nonantigenic place-holding lipids that provide a hydrophobic substrate for the initial folding reactions and serve a groove-blocking function until antigenic exogenous lipids are encountered in acidic endosomes.…”

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confidence: 92%

Discovery of deoxyceramides and diacylglycerols as CD1b scaffold lipids among diverse groove-blocking lipids of the human CD1 system

Huang

Cheng

Young

et al. 2011

102

Unlike the dominant role of one class II invariant chain peptide (CLIP) in blocking MHC class II, comparative lipidomics analysis shows that human cluster of differentiation (CD) proteins CD1a, CD1b, CD1c, and CD1d bind lipids corresponding to hundreds of diverse accurate mass retention time values. Although most ions were observed in association with several CD1 proteins, ligands binding selectively to one CD1 isoform allowed the study of how differing antigenbinding grooves influence lipid capture. Although the CD1b groove is distinguished by its unusually large volume (2,200 Å 3 ) and the T′ tunnel, the average mass of compounds eluted from CD1b was similar to that of lipids from CD1 proteins with smaller grooves. Elution of small ligands from the large CD1b groove might be explained if two small lipids bind simultaneously in the groove. Crystal structures indicate that all CD1 proteins can capture one antigen with its hydrophilic head group exposed for T-cell recognition, but CD1b structures show scaffold lipids seated below the antigen. We found that ligands selectively associated with CD1b lacked the hydrophilic head group that is generally needed for antigen recognition but interferes with scaffold function. Furthermore, we identified the scaffolds as deoxyceramides and diacylglycerols and directly demonstrate a function in augmenting presentation of a small glycolipid antigen to T cells. Thus, unlike MHC class II, CD1 proteins capture highly diverse ligands in the secretory pathway. CD1b has a mechanism for presenting either two small or one large lipid, allowing presentation of antigens with an unusually broad range of chain lengths.antigen presentation | Mycobacterium tuberculosis | cluster of differentiation 1

“…The recombinant human CD1d molecules used in our cell-free assays are purified from HEK293T cells and are loaded with a spectrum of cell lipids derived from the ER, Golgi, and secretory compartment (55), some of which are reported to be antigenic for human iNKT cells (56). Therefore, the capacity of lipid-bound saposin B to load these recombinant CD1d molecules also implied its ability to promote lipid exchange.…”

Section: Discussionmentioning

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

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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