Crucial amino acid residues of mouse CD1d for glycolipid ligand presentation to Vα14 NKT cells

Kamada, Noriaki; Iijima, Hiroshi; Kimura, Kaname; Harada, Michishige; Shimizu, Eihan; Motohashi, Shinichiro; Kawano, Tetsu; Shinkai, Hiroshi; Nakayama, Toshinori; Sakai, Teruyuki; Brossay, Laurent; Kronenberg, Mitchell; Taniguchi, Masaru

doi:10.1093/intimm/13.7.853

Cited by 52 publications

(32 citation statements)

References 41 publications

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“…Therefore, the a-1,3-linked galactose of the iGb3 or 4 000 -dh-iGb3 was not visible in the crystal structure. Consistent with the previous reports (25,26), the docking model showed that the acyl chain of 4 000 -dhiGb3 could insert to the pocket A 0 by forming hydrophobic interactions with this subsite, and the sphingosine chain could insert into the F 0 pocket by forming hydrophobic interactions. Meanwhile, the hydrophilic phenyl group close to the 2 chains could interact with the rip compartment of the CD1d binding groove (Fig.…”

Section: Expression Of T-bet In Nkt Cells and Thus Resulted In Greatesupporting

confidence: 89%

Enhanced Antitumor Effects by Chemical Modified IGb3 Analogues

Zhou

Zhang²,

Xia³

et al. 2011

Molecular Cancer Therapeutics

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Certain glycolipid antigens for natural killer T (NKT) cells can direct the overall cytokine balance of the immune response. However, the molecular mechanism of Th1-or Th2-biased cytokine secretion by NKT cells is still unknown. Previously, we synthesized isoglobotrihexosylceramide (iGb3) analogues by introducing a hydroxyl group at C4 on the ceramide portion of iGb3 to produce 4-HO-iGb3 or to further deoxylation on the terminal galactose to produce 4 000 -dh-iGb3. Both modified iGb3, especially 4 000 -dh-iGb3, stimulated more IFN-g production by hepatic NKT cells, and thus elicited preferential Th1 responses. Here, we found that 4 000 -dh-iGb3-loaded bone marrow-derived dendritic cells (DC) could significantly inhibit growth of subcutaneous melanoma and suppress lung metastasis in C57BL/6 mice compared with unmodified iGb3-loaded DCs. In investigating the mechanisms of this improved activity, we found that 4 000 -dh-iGb3 stimulation increased STAT1 signaling by NKT cells, whereas the phosphorylation of Th2 type cytokine-associated transcription factor STAT6 signaling was not affected. Analysis of the structures of iGb3 and 4 000 -dh-iGb3 revealed that 4 000 -dh-iGb3 provides greater stability and affinity between glycolipid and CD1d or NKT TCR complex than iGb3. Thus, 4 000 -dh-iGb3 can improve the antitumor effects of a DC-

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Section: Expression Of T-bet In Nkt Cells and Thus Resulted In Greatesupporting

confidence: 89%

Enhanced Antitumor Effects by Chemical Modified IGb3 Analogues

Zhou

Zhang²,

Xia³

et al. 2011

Molecular Cancer Therapeutics

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“…The hydrophilic portion of the Ag can interact with the surface residues of CD1d, effectively modifying the character of the surface presented for recognition to the TCR. Structure-based mutagenesis studies identified several residues of mCD1d that affect recognition of CD1/␣GalCer complexes by iNKT cells (38,48). Together with the present structure, we can finely dissect the contributions of these mutated residues to interaction with Ag or the TCR.…”

Section: Discussionmentioning

confidence: 64%

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

Giabbai¹,

Sidobre²,

Crispin

et al. 2005

The Journal of Immunology

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116

108

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NKT cells are immunoregulatory lymphocytes whose activation is triggered by the recognition of lipid Ags in the context of the CD1d molecules by the TCR. In this study we present the crystal structure to 2.8 Å of mouse CD1d bound to phosphatidylcholine. The interactions between the ligand acyl chains and the CD1d molecule define the structural and chemical requirements for the binding of lipid Ags to CD1d. The orientation of the polar headgroup toward the C terminus of the α1 helix provides a rationale for the structural basis for the observed Vα chain bias in invariant NKT cells. The contribution of the ligand to the protein surface suggests a likely mode of recognition of lipid Ags by the NKT cell TCR.

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“…We and others have generated transfected cell lines expressing nonconservative mutations at positions 79 and 80 or 150 and 153 and were able to demonstrate that these changes have important effects on the ability to stimulate NKT cells (42,49). To investigate these effects at a molecular level, we produced native soluble forms of the mutant CD1d molecules and, using a surface plasmon resonance assay, we demonstrated that they retain nearly equivalent ability to bind immobilized biotin ␣-GalCer.…”

Section: Discussionmentioning

confidence: 99%

The Vα14 NKT Cell TCR Exhibits High-Affinity Binding to a Glycolipid/CD1d Complex

Sidobre

Naidenko

Sim

et al. 2002

The Journal of Immunology

Self Cite

116

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Most CD1d-dependent NKT cells in mice have a canonical Vα14Jα18 TCR rearrangement. However, relatively little is known concerning the molecular basis for their reactivity to glycolipid Ags presented by CD1d. Using glycolipid Ags, soluble forms of a Vα14 NKT cell-derived TCR, and mutant and wild-type CD1d molecules, we probed the TCR/CD1d interaction by surface plasmon resonance, tetramer equilibrium staining, and tetramer staining decay experiments. By these methods, several CD1d α-helical amino acids could be defined that do not greatly alter lipid binding, but that affect the interaction with the TCR. Binding of the Vα14+ TCR to CD1d requires the agonist α-galactosylceramide (α-GalCer), as opposed to the nonantigenic β-galactosylceramide, although both Ags bind to CD1d, indicating that the carbohydrate moiety of the CD1d-bound Ag plays a major role in the TCR interaction. The TCR has a relatively high-affinity binding to the α-GalCer/CD1d complex, with a particularly slow off rate. These unique properties are consistent with the coreceptor-independent action of the Vα14 TCR and may be related to the intense response to α-GalCer by NKT cells in vivo.

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Crucial amino acid residues of mouse CD1d for glycolipid ligand presentation to Vα14 NKT cells

Cited by 52 publications

References 41 publications

Enhanced Antitumor Effects by Chemical Modified IGb3 Analogues

Enhanced Antitumor Effects by Chemical Modified IGb3 Analogues

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

The Vα14 NKT Cell TCR Exhibits High-Affinity Binding to a Glycolipid/CD1d Complex

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