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

28 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Wun, K. S., Ross, F., Patel, O., Besra, G. S., Porcelli, S. A., Richardson, S. K., Keshipeddy, S., Howell, A. R., Godfrey, D. I., & 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, 287(46), 39139-39148. https://doi.org/10.1074/jbc.M112.412320