Crystal Structure of Mouse CD1d Bound to the Self Ligand Phosphatidylcholine: A Molecular Basis for NKT Cell Activation

Giabbai, Barbara; Sidobre, Stéphane; Crispin, Max; Sanchez-Ruiz, Yovan; Bachi, Ángela; Kronenberg, Mitchell; Wilson, Ian A.; Degano, Massimo

doi:10.4049/jimmunol.175.2.977

Cited by 116 publications

(112 citation statements)

References 58 publications

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“…The overall architecture of mouse CD1d and its hydrophobic binding groove have previously been described in detail (18,24,42). The bound PIM2 is remarkably ordered in the binding groove, despite its large carbohydrate headgroup that extends away from the surface of CD1d.…”

Section: Structural Features Of the Mouse Cd1d-pim2 Complexmentioning

confidence: 95%

“…Various foreign ligands can activate iNKT cells, such as the nonmammalian glycolipid, ␣-galactosylceramide (␣-GalCer) (12), microbial ␣-glycuronosylceramides (13,14) (containing either glucuronic acid or galacturonic acid (GalA-GSL)), mycobacterial PIM4 (15), as well as the self-ligand isoglobotrihexosylceramide (iGB3) (16). Crystal structures of CD1d in complex with ␣-GalCer or GalA-GSL (17)(18)(19) have revealed the exquisite hydrogen-bonding network between the ␣-linked carbohydrate headgroup and CD1d, which has not been seen in any other CD1 complex, including human CD1a-sulfatide (20), CD1a-lipopeptide (21), CD1b-PI (22), CD1b-glucosemonomycolate (23), or mouse CD1d-phosphatidylcholine (CD1d-PC) (24).…”

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confidence: 99%

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Structural Characterization of Mycobacterial Phosphatidylinositol Mannoside Binding to Mouse CD1d

Zajonc

Ainge²,

Painter³

et al. 2006

The Journal of Immunology

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Mycobacterial phosphatidylinositol tetramannosides (PIM4) are agonists for a distinct population of invariant human (Vα24) and mouse (Vα14) NKT cells, when presented by CD1d. We determined the crystal structure at 2.6-Å resolution of mouse CD1d bound to a synthetic dipalmitoyl-PIM2. Natural PIM2, which differs in its fatty acid composition is a biosynthetic precursor of PIM4, PIM6, lipomannan, and lipoarabinomannan. The PIM2 headgroup (inositol-dimannoside) is the most complex to date among all the crystallized CD1d ligands and is remarkably ordered in the CD1d binding groove. A specific hydrogen-bonding network between PIM2 and CD1d orients the headgroup in the center of the binding groove and above the A′ pocket. A central cluster of hydrophilic CD1d residues (Asp153, Thr156, Ser76, Arg79) interacts with the phosphate, inositol, and α1–α6-linked mannose of the headgroup, whereas additional specificity for the α1- and α2-linked mannose is conferred by Thr159. The additional two mannoses in PIM4, relative to PIM2, are located at the distal 6′ carbon of the α1-α6-linked mannose and would project away from the CD1d binding groove for interaction with the TCR. Compared with other CD1d-sphingolipid structures, PIM2 has an increased number of polar interactions between its headgroup and CD1, but reduced specificity for the diacylglycerol backbone. Thus, novel NKT cell agonists can be designed that focus on substitutions of the headgroup rather than on reducing lipid chain length, as in OCH and PBS-25, two potent variants of the highly stimulatory invariant NKT cell agonist α-galactosylceramide.

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Section: Structural Features Of the Mouse Cd1d-pim2 Complexmentioning

confidence: 95%

mentioning

confidence: 99%

Structural Characterization of Mycobacterial Phosphatidylinositol Mannoside Binding to Mouse CD1d

Zajonc

Ainge²,

Painter³

et al. 2006

The Journal of Immunology

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“…72,83 Several glycosphingolipids and phospholipids derived from mammalian, bacterial, protozoan and plant species have been identified as possible natural ligands for NKT cells, 84,85 and phospholipids, such as phosphatidylcholine and phosphatidylinositol. 86,87 The semi-invariant TCRs can recognize iGb3 (isoglobotrihexosylceramide), a mammalian glycosphingolipid, and a microbial a-glycuronylceramide found in the cell wall of Gram-negative, lipopolysaccharide-negative bacteria. 88 iGb3 has been proposed as one of the molecules recognized by NKT cells under pathological conditions, such as cancer and autoimmune disease.…”

Section: Mechanisms Of Action Of Gcmentioning

confidence: 99%

Glucocerebroside: an evolutionary advantage for patients with Gaucher disease and a new immunomodulatory agent

2009

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Gaucher disease (GD) is caused by the reduced activity of a lysosomal enzyme, glucocerebrosidase, leading to the accumulation of glucocerebroside (GC). The relatively high prevalence of this disease within an ethnic group is believed to reflect a selective advantage. Treatment with enzyme replacement therapy (ERT) is safe and effective in ameliorating the primary symptoms of the disease, yet there have been reports that some patients on ERT have developed type 2 diabetes or metabolic syndrome, malignancies and central nervous system disorders. A series of animal studies suggest that these complications may be related to the reduction of GC levels by the enzyme administered. GC has been shown to have an immunomodulatory effect through the promotion of dendritic cells, natural killer T cells, and regulatory T cells. The break down of GC to ceramide can underline part of these findings. Clinical trials suggested a beneficial effect of GC in type 2 diabetes or nonalcoholic steatohepatitis. This review of the data from animal models and humans proposes that the increased level of GC may provide an evolutionary advantage for patients with GD. Indirectly, these data support treating symptomatic patients with mild/moderate GD with lowdose ERT and re-evaluating the use of ERT in asymptomatic patients.

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“…CD1b binds PC together with a 42-44 carbon-long molecule that remains embedded into the lipid-binding groove [25]. Mouse CD1d associates with PC and a C 16 -long fatty acid [32,38]. These spacers partially occupy one lipid-binding pocket, still allowing accommodation of lipids with short acyl chains.…”

Section: Trafficking Of Cd1 Molecules and Antigen Loading In Differenmentioning

confidence: 99%

“…The ER membrane is thinner than other cell membranes, is poor in lipids that facilitate its packing and thus allows fast translocation of PL even in the absence of dedicated flippases. This mechanism may explain why PC, which is one of the most abundant PL, associates with nascent CD1b and CD1d molecules [25,32]. Ceramide, which constitutes the apolar component of GSL, is also synthesized on the cytoplasmic leaflet of ER and then transported to the cytoplasmic leaflet of cis-Golgi membranes where glucosylceramide is synthesized.…”

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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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Crystal Structure of Mouse CD1d Bound to the Self Ligand Phosphatidylcholine: A Molecular Basis for NKT Cell Activation

Cited by 116 publications

References 58 publications

Structural Characterization of Mycobacterial Phosphatidylinositol Mannoside Binding to Mouse CD1d

Structural Characterization of Mycobacterial Phosphatidylinositol Mannoside Binding to Mouse CD1d

Glucocerebroside: an evolutionary advantage for patients with Gaucher disease and a new immunomodulatory agent

The cellular and biochemical rules of lipid antigen presentation

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