Kinetics and Cellular Site of Glycolipid Loading Control the Outcome of Natural Killer T Cell Activation

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CD1e is a member of the CD1 family that participates in lipid antigen presentation without interacting with the T-cell receptor. It binds lipids in lysosomes and facilitates processing of complex glycolipids, thus promoting editing of lipid antigens. We find that CD1e may positively or negatively affect lipid presentation by CD1b, CD1c, and CD1d. This effect is caused by the capacity of CD1e to facilitate rapid formation of CD1-lipid complexes, as shown for CD1d, and also to accelerate their turnover. Similar results were obtained with antigen-presenting cells from CD1e transgenic mice in which lipid complexes are assembled more efficiently and show faster turnover than in WT antigen-presenting cells. These effects maximize and temporally narrow CD1-restricted responses, as shown by reactivity to Sphingomonas paucimobilis-derived lipid antigens. CD1e is therefore an important modulator of both group 1 and group 2 CD1-restricted responses influencing the lipid antigen availability as well as the generation and persistence of CD1-lipid complexes.CD1 restriction | lipid transfer proteins | natural killer T cells

Section: Facilitated Presentation Of Lipid Antigens In Cd1e Transgenisupporting

confidence: 53%

Section: Cd1e Effects On Exogenous Glycolipid Antigen Presentation Tomentioning

confidence: 99%

Fine tuning by human CD1e of lipid-specific immune responses

Facciotti

Cavallari

Angénieux

et al. 2011

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“…In particular, CD1b and CD1d are relatively resistant to exogenous antigen loading at neutral pH conditions normally found in the secretory pathway (3)(4)(5)(6). They more rapidly exchange antigens at pH 4-6, which is characteristic of the late endosomal or lysosomal environment (7,8). The differing pH requirements for antigen loading, combined with enrichment of endogenous lipids in the secretory pathway and exogenous lipids endosomes, are coalescing into a two-step model of lipid antigen presentation.…”

mentioning

confidence: 99%

“…Second, upon reaching the endosomes by recycling or direct routes, the acidic pH facilitates the unfolding or untethering of the parallel α-helices that normally restrict ligand access to the groove (3-6). Increased groove access promotes both unloading of the initially bound endogenous lipids and subsequent capture of the exogenous lipids delivered by infection, lipid transfer proteins, or receptor-mediated uptake (8,10).…”

mentioning

confidence: 99%

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

“…Despite high homology, the four saposins have different lipid specificities, as demonstrated by the phenotype of patients with selective deficiency of individual molecules (53). We limited our study to the role of saposin B, because evidence from our own works and from the literature (8,11,32) suggested its dominant role in loading soluble lipids onto CD1d molecules. We determined the binding affinity of saposin B to a radiolabeled version of ThrCer at pH5 and pH7 (1.8 μM and 4.5 μM, respectively), and observed that it reached a plateau when saposin B was present in molar excess.…”

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