Human and mouse type I natural killer T cell antigen receptors exhibit different fine specificities for CD1d-antigen complex

Kwok S. Wun, Fiona Ross, Onisha Patel, Gurdyal S. Besra, Steven A. Porcelli, Stewart K. Richardson, Santosh Keshipeddy, Amy R. Howell, Dale I. Godfrey, Jamie Rossjohn

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Human and mouse type I natural killer T (NKT) cells respond to a variety of CD1d-restricted glycolipid antigens (Ags), with their NKT cell antigen receptors (NKT TCRs) exhibiting reciprocal cross-species reactivity that is underpinned by a conserved NKT TCR-CD1d-Ag docking mode. Within this common docking footprint, the NKT TCR recognizes, to varying degrees of affinity, a range of Ags. Presently, it is unclear whether the human NKT TCRs will mirror the generalities underpinning the fine specificity of the mouse NKT TCR-CD1d-Ag interaction. Here, we assessed human NKT TCR recognition against altered glycolipid ligands of α-galactosylceramide (α-GalCer) and have determined the structures of a human NKT TCR in complex with CD1d-4′,4″-deoxy-α-GalCer and CD1d-α-GalCer with a shorter, di-unsaturated acyl chain (C20:2). Altered glycolipid ligands with acyl chain modifications did not affect the affinity of the human NKT TCR-CD1d-Ag interaction. Surprisingly, human NKT TCR recognition is more tolerant to modifications at the 4′-OH position in comparison with the 3′-OH position of α-GalCer, which contrasts the fine specificity of the mouse NKT TCR-CD1d-Ag recognition (4′-OH > 3′-OH). The fine specificity differences between human and mouse NKT TCRs was attributable to differing interactions between the respective complementarity-determining region 1α loops and the Ag. Accordingly, germline encoded fine-specificity differences underpin human and mouse type I NKT TCR interactions, which is an important consideration for therapeutic development and NKT cell physiology.

Original languageEnglish (US)
Pages (from-to)39139-39148
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number46
DOIs
StatePublished - Nov 9 2012

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CD1d Antigen
Natural Killer T-Cells
Glycolipids
T-Cell Antigen Receptor
T-cells
Galactosylceramides
Ligands
Complementarity Determining Regions
Antigens
Physiology
Mirrors
Cell Physiological Phenomena

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Human and mouse type I natural killer T cell antigen receptors exhibit different fine specificities for CD1d-antigen complex. / Wun, Kwok S.; Ross, Fiona; Patel, Onisha; Besra, Gurdyal S.; Porcelli, Steven A.; Richardson, Stewart K.; Keshipeddy, Santosh; Howell, Amy R.; Godfrey, Dale I.; Rossjohn, Jamie.

In: Journal of Biological Chemistry, Vol. 287, No. 46, 09.11.2012, p. 39139-39148.

Research output: Contribution to journalArticle

Wun, KS, Ross, F, Patel, O, Besra, GS, Porcelli, SA, Richardson, SK, Keshipeddy, S, Howell, AR, Godfrey, DI & Rossjohn, J 2012, 'Human and mouse type I natural killer T cell antigen receptors exhibit different fine specificities for CD1d-antigen complex', Journal of Biological Chemistry, vol. 287, no. 46, pp. 39139-39148. https://doi.org/10.1074/jbc.M112.412320
Wun, Kwok S. ; Ross, Fiona ; Patel, Onisha ; Besra, Gurdyal S. ; Porcelli, Steven A. ; Richardson, Stewart K. ; Keshipeddy, Santosh ; Howell, Amy R. ; Godfrey, Dale I. ; Rossjohn, Jamie. / Human and mouse type I natural killer T cell antigen receptors exhibit different fine specificities for CD1d-antigen complex. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 46. pp. 39139-39148.
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abstract = "Human and mouse type I natural killer T (NKT) cells respond to a variety of CD1d-restricted glycolipid antigens (Ags), with their NKT cell antigen receptors (NKT TCRs) exhibiting reciprocal cross-species reactivity that is underpinned by a conserved NKT TCR-CD1d-Ag docking mode. Within this common docking footprint, the NKT TCR recognizes, to varying degrees of affinity, a range of Ags. Presently, it is unclear whether the human NKT TCRs will mirror the generalities underpinning the fine specificity of the mouse NKT TCR-CD1d-Ag interaction. Here, we assessed human NKT TCR recognition against altered glycolipid ligands of α-galactosylceramide (α-GalCer) and have determined the structures of a human NKT TCR in complex with CD1d-4′,4″-deoxy-α-GalCer and CD1d-α-GalCer with a shorter, di-unsaturated acyl chain (C20:2). Altered glycolipid ligands with acyl chain modifications did not affect the affinity of the human NKT TCR-CD1d-Ag interaction. Surprisingly, human NKT TCR recognition is more tolerant to modifications at the 4′-OH position in comparison with the 3′-OH position of α-GalCer, which contrasts the fine specificity of the mouse NKT TCR-CD1d-Ag recognition (4′-OH > 3′-OH). The fine specificity differences between human and mouse NKT TCRs was attributable to differing interactions between the respective complementarity-determining region 1α loops and the Ag. Accordingly, germline encoded fine-specificity differences underpin human and mouse type I NKT TCR interactions, which is an important consideration for therapeutic development and NKT cell physiology.",
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AU - Porcelli, Steven A.

AU - Richardson, Stewart K.

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AU - Rossjohn, Jamie

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