Structural Basis for the Recognition of C20:2-αGalCer by the Invariant Natural Killer T Cell Receptor-like Antibody L363

Yu, Esther Dawen; Gottardi, Enrico; Wang, Jing; Mac, Thien-Thi; Yu, Karl O. A.; Calenbergh, Serge Van; Porcelli, Steven A.; Zajonc, Dirk M.

doi:10.1074/jbc.m111.308783

Cited by 23 publications

(26 citation statements)

References 53 publications

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“…Both antibodies are specific to the complex CD1d-α-GalCer (Yu et al, 2007). The crystal structure of CD1d-α-GalCer in complex with L363 shows how the antibody can see both CD1 and the α-linked sugar (Yu et al, 2012). We used this structure to demonstrate by modeling that L363 could not bind β-linked glycolipids or diglycosylceramides because of obvious steric hindrances and that galactose was seen better than glucose as a result of a unique hydrogen bond between the C4 hydroxyl group of the sugar and the antibody (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

The Identification of the Endogenous Ligands of Natural Killer T Cells Reveals the Presence of Mammalian α-Linked Glycosylceramides

et al. 2014

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Summary Glycosylceramides in mammalian species are thought to be present in the form of β-anomers. This conclusion was reinforced by the identification of only one glucosylceramide and one galactosylcerhamide synthase, both β-transferases, in mammalian genomes. Thus, the possibility that small amounts of α-anomers could be produced by an alternative enzymatic pathway, by an unfaithful enzyme, or spontaneously in unusual cellular compartments has not been examined in detail. We approached the question by taking advantage of the exquisite specificity of T and B lymphocytes and combined it with the specificity of catabolic enzymes of the sphingolipid pathway. Here, we demonstrate that mammalian immune cells produce constitutively very small quantities of α-glycosylceramides, which are the major endogenous ligands of natural killer T cells. Catabolic enzymes of the ceramide and glycolipid pathway tightly control the amount of these α-glycosylceramides. The exploitation of this pathway to manipulate the immune response will create new therapeutic opportunities.

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Section: Resultsmentioning

confidence: 99%

The Identification of the Endogenous Ligands of Natural Killer T Cells Reveals the Presence of Mammalian α-Linked Glycosylceramides

et al. 2014

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“…This result is consistent with a rare, GCase-resistant activating lipid with decreased competition for CD1d binding sites following digestion. The L363 monoclonal antibody was developed to recognize α-galactosylceramide bound to CD1d, and has proved a valuable tool for tracking α-galactosylceramide and other α-galactosphingolipids bound to CD1d (20,21). α-GlcCer recognition by L363 has not been previously reported, and we were able to demonstrate binding of this reagent to CD1d-transfected RAW 246.7 cells loaded with α-GlcCer (Fig.…”

Section: Resultsmentioning

confidence: 71%

Activation of iNKT cells by a distinct constituent of the endogenous glucosylceramide fraction

Brennan

Tatituri

Heiß

et al. 2014

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

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Significance Invariant natural killer T (iNKT) cells are a specialized subset of T cells that recognizes lipids, rather than peptides, as antigens. Recognition of both endogenous and exogenous lipids by iNKT cells contributes to immune responses during infection, cancer, autoimmune disease, and allergic disease. The endogenous lipids recognized by iNKT cells in most contexts, however, remain unclear. In this report, we characterize the lipid antigen activity found in mammalian milk and tissues. Our data suggest that activity is related to a minor component of the glucosylceramide fraction. Whether contributed from endogenous sources or from the diet, this rare, yet potent lipid activity may play an important role in driving immune responses.

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“…El primer análogo funcionalmente distinto de αGalCer fue identificado como OCH, el cual produce una respuesta con tendencia al tipo Th2 similar a otros análogos como C20:2, que tiene una cadena acilada más corta e insaturada (26,27). Por otro lado, el compuesto α-C-GalCer (tabla 1), que tiene un remplazo del oxígeno de unión al azúcar por un carbono, produce una respuesta con tendencia al tipo Th1 (28).…”

Section: Antígenos Lipídicos Sintéticosunclassified

Mecanismos de activación de las células T asesinas naturales invariantes (iNKT)

Baena

Gómez-Giraldo

Carreño

2015

iatreia

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RESUMENAunque se ha logrado un conocimiento amplio acerca de las células T asesinas naturales (iNKT), aún no existe consenso sobre sus mecanismos de activación. Dichas células reconocen diferentes antígenos glicolipídicos presentados por medio de la molécula CD1d, los cuales pueden ser endógenos, exógenos derivados de organismos como bacterias y sintéticos desarrollados para aplicaciones clínicas. Existe mucho interés en entender cómo estas distintas variantes glicolipídicas inducen diferentes tipos de polarización, pero ha sido muy difícil llegar a un consenso, debido a que la respuesta depende de varios factores como la naturaleza, la internalización y el procesamiento de los glicolípidos. Además, la activación de las células iNKT la determinan el tipo y estado de activación de la célula presentadora de antígeno, las moléculas coestimuladoras, los mecanismos de transactivación y la localización de los complejos CD1d-glicolípido en distintas microrregiones de la membrana plasmática, como las balsas lipídicas. Esta revisión explora la evidencia sobre los factores que afectan la activación de las células iNKT con el fin de entender su potencial inmunomodulador. PALABRAS CLAVEα-Galactosilceramida; Células Inkt; CD1d; Glicolípidos; Presentación Antigénica; TCR SUMMARY Activation mechanisms of invariant natural killer T cells (iNKTs)A great amount of knowledge on natural killer T cells (iNKTs) is now available, but a consensus about their activation mechanisms has not been reached. These cells recognize different glycolipid antigens through the CD1d molecule. Such antigens may be endogenous, derived from

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Structural Basis for the Recognition of C20:2-αGalCer by the Invariant Natural Killer T Cell Receptor-like Antibody L363

Cited by 23 publications

References 53 publications

The Identification of the Endogenous Ligands of Natural Killer T Cells Reveals the Presence of Mammalian α-Linked Glycosylceramides

The Identification of the Endogenous Ligands of Natural Killer T Cells Reveals the Presence of Mammalian α-Linked Glycosylceramides

Activation of iNKT cells by a distinct constituent of the endogenous glucosylceramide fraction

Mecanismos de activación de las células T asesinas naturales invariantes (iNKT)

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