Document Detail

CD1d protein structure determines species-selective antigenicity of isoglobotrihexosylceramide (iGb3) to invariant NKT cells.
MedLine Citation:
PMID:  23280365     Owner:  NLM     Status:  MEDLINE    
Isoglobotrihexosylceramide (iGb3) has been identified as a potent CD1d-presented self-antigen for mouse invariant natural killer T (iNKT) cells. The role of iGb3 in humans remains unresolved, however, as there have been conflicting reports about iGb3-dependent human iNKT-cell activation, and humans lack iGb3 synthase, a key enzyme for iGb3 synthesis. Given the importance of human immune responses, we conducted a human-mouse cross-species analysis of iNKT-cell activation by iGb3-CD1d. Here we show that human and mouse iNKT cells were both able to recognise iGb3 presented by mouse CD1d (mCD1d), but not human CD1d (hCD1d), as iGb3-hCD1d was unable to support cognate interactions with the iNKT-cell TCRs tested in this study. The structural basis for this discrepancy was identified as a single amino acid variation between hCD1d and mCD1d, a glycine-to-tryptophan modification within the α2-helix that prevents flattening of the iGb3 headgroup upon TCR ligation. Mutation of the human residue, Trp153, to the mouse ortholog, Gly155, therefore allowed iGb3-hCD1d to stimulate human iNKT cells. In conclusion, our data indicate that iGb3 is unlikely to be a major antigen in human iNKT-cell biology.
Joseph P Sanderson; Patrick J Brennan; Salah Mansour; Gediminas Matulis; Onisha Patel; Nikolai Lissin; Dale I Godfrey; Kazuyoshi Kawahara; Ulrich Zähringer; Jamie Rossjohn; Michael B Brenner; Stephan D Gadola
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-31
Journal Detail:
Title:  European journal of immunology     Volume:  43     ISSN:  1521-4141     ISO Abbreviation:  Eur. J. Immunol.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-13     Completed Date:  2013-05-02     Revised Date:  2014-03-26    
Medline Journal Info:
Nlm Unique ID:  1273201     Medline TA:  Eur J Immunol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  815-25     Citation Subset:  IM    
Copyright Information:
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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MeSH Terms
Amino Acids
Antigen Presentation
Antigens, CD1d / chemistry,  immunology*,  metabolism
Globosides / immunology*,  metabolism
Lymphocyte Activation / immunology
Models, Molecular
Natural Killer T-Cells / immunology*
Protein Binding
Protein Conformation
Protein Interaction Domains and Motifs
Receptors, Antigen, T-Cell / metabolism
Species Specificity
Trihexosylceramides / immunology*,  metabolism
Grant Support
Reg. No./Substance:
0/Amino Acids; 0/Antigens, CD1d; 0/Globosides; 0/Receptors, Antigen, T-Cell; 0/Trihexosylceramides; 0/isoglobotrihexosylceramide

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