A minimal binding footprint on CD1d-glycolipid is a basis for selection of the unique human NKT TCR

Kwok Soon Wun, Natalie Borg, Lars Kjer-Nielsen, Travis Clarke Beddoe, Ruide Koh, Stewart K Richardson, Meena Thakur, Amy R Howell, James P Scott-Browne, Laurent Gapin, Dale I Godfrey, James McCluskey, Jamie Rossjohn

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Abstract

Although it has been established how CD1 binds a variety of lipid antigens (Ag), data are only now emerging that show how alphabeta T cell receptors (TCRs) interact with CD1-Ag. Using the structure of the human semiinvariant NKT TCR-CD1d-alpha-galactosylceramide (alpha-GalCer) complex as a guide, we undertook an alanine scanning mutagenesis approach to define the energetic basis of this interaction between the NKT TCR and CD1d. Moreover, we explored how analogues of alpha-GalCer affected this interaction. The data revealed that an identical energetic footprint underpinned the human and mouse NKT TCR-CD1d-alpha-GalCer cross-reactivity. Some, but not all, of the contact residues within the Jalpha18-encoded invariant CDR3alpha loop and Vbeta11-encoded CDR2beta loop were critical for recognizing CD1d. The residues within the Valpha24-encoded CDR1alpha and CDR3alpha loops that contacted the glycolipid Ag played a smaller energetic role compared with the NKT TCR residues that contacted CD1d. Collectively, our data reveal that the region distant to the protruding Ag and directly above the F pocket of CD1d was the principal factor in the interaction with the NKT TCR. Accordingly, although the structural footprint at the NKT TCR-CD1d-alpha-GalCer is small, the energetic footprint is smaller still, and reveals the minimal requirements for CD1d restriction.
Original languageEnglish
Pages (from-to)939 - 949
Number of pages11
JournalJournal of Experimental Medicine
Volume205
Issue number4
Publication statusPublished - 2008

Cite this

Wun, Kwok Soon ; Borg, Natalie ; Kjer-Nielsen, Lars ; Beddoe, Travis Clarke ; Koh, Ruide ; Richardson, Stewart K ; Thakur, Meena ; Howell, Amy R ; Scott-Browne, James P ; Gapin, Laurent ; Godfrey, Dale I ; McCluskey, James ; Rossjohn, Jamie. / A minimal binding footprint on CD1d-glycolipid is a basis for selection of the unique human NKT TCR. In: Journal of Experimental Medicine. 2008 ; Vol. 205, No. 4. pp. 939 - 949.
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title = "A minimal binding footprint on CD1d-glycolipid is a basis for selection of the unique human NKT TCR",
abstract = "Although it has been established how CD1 binds a variety of lipid antigens (Ag), data are only now emerging that show how alphabeta T cell receptors (TCRs) interact with CD1-Ag. Using the structure of the human semiinvariant NKT TCR-CD1d-alpha-galactosylceramide (alpha-GalCer) complex as a guide, we undertook an alanine scanning mutagenesis approach to define the energetic basis of this interaction between the NKT TCR and CD1d. Moreover, we explored how analogues of alpha-GalCer affected this interaction. The data revealed that an identical energetic footprint underpinned the human and mouse NKT TCR-CD1d-alpha-GalCer cross-reactivity. Some, but not all, of the contact residues within the Jalpha18-encoded invariant CDR3alpha loop and Vbeta11-encoded CDR2beta loop were critical for recognizing CD1d. The residues within the Valpha24-encoded CDR1alpha and CDR3alpha loops that contacted the glycolipid Ag played a smaller energetic role compared with the NKT TCR residues that contacted CD1d. Collectively, our data reveal that the region distant to the protruding Ag and directly above the F pocket of CD1d was the principal factor in the interaction with the NKT TCR. Accordingly, although the structural footprint at the NKT TCR-CD1d-alpha-GalCer is small, the energetic footprint is smaller still, and reveals the minimal requirements for CD1d restriction.",
author = "Wun, {Kwok Soon} and Natalie Borg and Lars Kjer-Nielsen and Beddoe, {Travis Clarke} and Ruide Koh and Richardson, {Stewart K} and Meena Thakur and Howell, {Amy R} and Scott-Browne, {James P} and Laurent Gapin and Godfrey, {Dale I} and James McCluskey and Jamie Rossjohn",
year = "2008",
language = "English",
volume = "205",
pages = "939 -- 949",
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Wun, KS, Borg, N, Kjer-Nielsen, L, Beddoe, TC, Koh, R, Richardson, SK, Thakur, M, Howell, AR, Scott-Browne, JP, Gapin, L, Godfrey, DI, McCluskey, J & Rossjohn, J 2008, 'A minimal binding footprint on CD1d-glycolipid is a basis for selection of the unique human NKT TCR', Journal of Experimental Medicine, vol. 205, no. 4, pp. 939 - 949.

A minimal binding footprint on CD1d-glycolipid is a basis for selection of the unique human NKT TCR. / Wun, Kwok Soon; Borg, Natalie; Kjer-Nielsen, Lars; Beddoe, Travis Clarke; Koh, Ruide; Richardson, Stewart K; Thakur, Meena; Howell, Amy R; Scott-Browne, James P; Gapin, Laurent; Godfrey, Dale I; McCluskey, James; Rossjohn, Jamie.

In: Journal of Experimental Medicine, Vol. 205, No. 4, 2008, p. 939 - 949.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A minimal binding footprint on CD1d-glycolipid is a basis for selection of the unique human NKT TCR

AU - Wun, Kwok Soon

AU - Borg, Natalie

AU - Kjer-Nielsen, Lars

AU - Beddoe, Travis Clarke

AU - Koh, Ruide

AU - Richardson, Stewart K

AU - Thakur, Meena

AU - Howell, Amy R

AU - Scott-Browne, James P

AU - Gapin, Laurent

AU - Godfrey, Dale I

AU - McCluskey, James

AU - Rossjohn, Jamie

PY - 2008

Y1 - 2008

N2 - Although it has been established how CD1 binds a variety of lipid antigens (Ag), data are only now emerging that show how alphabeta T cell receptors (TCRs) interact with CD1-Ag. Using the structure of the human semiinvariant NKT TCR-CD1d-alpha-galactosylceramide (alpha-GalCer) complex as a guide, we undertook an alanine scanning mutagenesis approach to define the energetic basis of this interaction between the NKT TCR and CD1d. Moreover, we explored how analogues of alpha-GalCer affected this interaction. The data revealed that an identical energetic footprint underpinned the human and mouse NKT TCR-CD1d-alpha-GalCer cross-reactivity. Some, but not all, of the contact residues within the Jalpha18-encoded invariant CDR3alpha loop and Vbeta11-encoded CDR2beta loop were critical for recognizing CD1d. The residues within the Valpha24-encoded CDR1alpha and CDR3alpha loops that contacted the glycolipid Ag played a smaller energetic role compared with the NKT TCR residues that contacted CD1d. Collectively, our data reveal that the region distant to the protruding Ag and directly above the F pocket of CD1d was the principal factor in the interaction with the NKT TCR. Accordingly, although the structural footprint at the NKT TCR-CD1d-alpha-GalCer is small, the energetic footprint is smaller still, and reveals the minimal requirements for CD1d restriction.

AB - Although it has been established how CD1 binds a variety of lipid antigens (Ag), data are only now emerging that show how alphabeta T cell receptors (TCRs) interact with CD1-Ag. Using the structure of the human semiinvariant NKT TCR-CD1d-alpha-galactosylceramide (alpha-GalCer) complex as a guide, we undertook an alanine scanning mutagenesis approach to define the energetic basis of this interaction between the NKT TCR and CD1d. Moreover, we explored how analogues of alpha-GalCer affected this interaction. The data revealed that an identical energetic footprint underpinned the human and mouse NKT TCR-CD1d-alpha-GalCer cross-reactivity. Some, but not all, of the contact residues within the Jalpha18-encoded invariant CDR3alpha loop and Vbeta11-encoded CDR2beta loop were critical for recognizing CD1d. The residues within the Valpha24-encoded CDR1alpha and CDR3alpha loops that contacted the glycolipid Ag played a smaller energetic role compared with the NKT TCR residues that contacted CD1d. Collectively, our data reveal that the region distant to the protruding Ag and directly above the F pocket of CD1d was the principal factor in the interaction with the NKT TCR. Accordingly, although the structural footprint at the NKT TCR-CD1d-alpha-GalCer is small, the energetic footprint is smaller still, and reveals the minimal requirements for CD1d restriction.

UR - http://www.ncbi.nlm.nih.gov/pubmed/18378792

M3 - Article

VL - 205

SP - 939

EP - 949

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 4

ER -