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Natural variations at position 93 of the invariant Va24-Ja18 alpha chain of human iNKT cell TCRs strongly impact on CD1d binding

Natural variations at position 93 of the invariant Va24-Ja18 alpha chain of human iNKT cell TCRs strongly impact on CD1d binding
Natural variations at position 93 of the invariant Va24-Ja18 alpha chain of human iNKT cell TCRs strongly impact on CD1d binding
Human invariant natural killer T (NKT) cell TCRs bind to CD1d via an "invariant" Vá24-Já18 chain (iNKTá) paired to semi-invariant V?11 chains (iNKTâ). Single-amino acid variations at position 93 (p93) of iNKTá, immediately upstream of the “invariant” CDR3á region, have been reported in a substantial proportion of human iNKT cell clones (4-30%). Although p93, a serine in most human iNKT cell TCRs, makes no contact with CD1d, it could affect CD1d-binding by altering the conformation of the crucial CDR3á loop. By generating recombinant refolded iNKT cell TCRs, we show that natural single-nucleotide variations in iNKTá, translating to serine, threonine, asparagine or isoleucine at p93, exert a powerful effect on CD1d binding, with up to 28-fold differences in affinity between these variants. This effect was observed with CD1d loaded with either the artificial á-galactosylceramide antigens KRN7000 or OCH, or the endogenous glycolipid â-galactosylceramide, and its importance for autoreactive recognition of endogenous lipids was demonstrated by the binding of variant iNKT cell TCR tetramers to cell-surface expressed CD1d. The serine-containing variant showed the strongest CD1d-binding, offering an explanation for its predominance in vivo. Complementary molecular dynamics modeling studies were consistent with an impact of p93 on the conformation of the CDR3á loop
iNKT cells, CD1d, tcr, surface plasmon resonance, molecular modelling
0014-2980
248-255
Sanderson, Joseph P.
55f9cdfc-ab1e-4b84-8c02-83c4d51cfcfe
Waldburger-Hauri, Kathrin
32aafc81-2aed-4813-abea-574851628d10
Garzon, Diana
f55bcf59-f74c-4e3c-902c-89324f68745a
Matulis, Gediminias
ce9b0ab6-35e7-4b92-a6a7-b3461ae38f3e
Mansour, Salah
4aecba5a-8387-4f7b-b766-0a9c309ccb8b
Pumphrey, Nicholas J.
24c90455-9799-4e01-9cc5-8da8b5098e19
Lissin, Nikolai
6352f824-8a86-4b00-9f54-78e01304613e
Villiger, Peter M.
3729cca4-f7e3-4a2d-a1af-c857649ea179
Jakobsen, Bent
bcdbcc12-c0ea-4c5a-bff7-bb6ac50597d5
Faraldo-Gomez, Jose D.
650c995b-ab19-418c-b785-42910e4045f1
Gadola, Stephan D.
ef2fa6cf-2ccc-4fea-a7a5-cc03a9d13ab1
Sanderson, Joseph P.
55f9cdfc-ab1e-4b84-8c02-83c4d51cfcfe
Waldburger-Hauri, Kathrin
32aafc81-2aed-4813-abea-574851628d10
Garzon, Diana
f55bcf59-f74c-4e3c-902c-89324f68745a
Matulis, Gediminias
ce9b0ab6-35e7-4b92-a6a7-b3461ae38f3e
Mansour, Salah
4aecba5a-8387-4f7b-b766-0a9c309ccb8b
Pumphrey, Nicholas J.
24c90455-9799-4e01-9cc5-8da8b5098e19
Lissin, Nikolai
6352f824-8a86-4b00-9f54-78e01304613e
Villiger, Peter M.
3729cca4-f7e3-4a2d-a1af-c857649ea179
Jakobsen, Bent
bcdbcc12-c0ea-4c5a-bff7-bb6ac50597d5
Faraldo-Gomez, Jose D.
650c995b-ab19-418c-b785-42910e4045f1
Gadola, Stephan D.
ef2fa6cf-2ccc-4fea-a7a5-cc03a9d13ab1

Sanderson, Joseph P., Waldburger-Hauri, Kathrin, Garzon, Diana, Matulis, Gediminias, Mansour, Salah, Pumphrey, Nicholas J., Lissin, Nikolai, Villiger, Peter M., Jakobsen, Bent, Faraldo-Gomez, Jose D. and Gadola, Stephan D. (2012) Natural variations at position 93 of the invariant Va24-Ja18 alpha chain of human iNKT cell TCRs strongly impact on CD1d binding. European Journal of Immunology, 42 (1), 248-255. (doi:10.1002/eji.201141956). (PMID:21956730)

Record type: Article

Abstract

Human invariant natural killer T (NKT) cell TCRs bind to CD1d via an "invariant" Vá24-Já18 chain (iNKTá) paired to semi-invariant V?11 chains (iNKTâ). Single-amino acid variations at position 93 (p93) of iNKTá, immediately upstream of the “invariant” CDR3á region, have been reported in a substantial proportion of human iNKT cell clones (4-30%). Although p93, a serine in most human iNKT cell TCRs, makes no contact with CD1d, it could affect CD1d-binding by altering the conformation of the crucial CDR3á loop. By generating recombinant refolded iNKT cell TCRs, we show that natural single-nucleotide variations in iNKTá, translating to serine, threonine, asparagine or isoleucine at p93, exert a powerful effect on CD1d binding, with up to 28-fold differences in affinity between these variants. This effect was observed with CD1d loaded with either the artificial á-galactosylceramide antigens KRN7000 or OCH, or the endogenous glycolipid â-galactosylceramide, and its importance for autoreactive recognition of endogenous lipids was demonstrated by the binding of variant iNKT cell TCR tetramers to cell-surface expressed CD1d. The serine-containing variant showed the strongest CD1d-binding, offering an explanation for its predominance in vivo. Complementary molecular dynamics modeling studies were consistent with an impact of p93 on the conformation of the CDR3á loop

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More information

Published date: January 2012
Keywords: iNKT cells, CD1d, tcr, surface plasmon resonance, molecular modelling
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 202081
URI: http://eprints.soton.ac.uk/id/eprint/202081
ISSN: 0014-2980
PURE UUID: 53fad456-9930-4010-81b6-358e339072d4
ORCID for Salah Mansour: ORCID iD orcid.org/0000-0002-5982-734X

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Date deposited: 03 Nov 2011 13:52
Last modified: 15 Mar 2024 03:32

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Contributors

Author: Joseph P. Sanderson
Author: Kathrin Waldburger-Hauri
Author: Diana Garzon
Author: Gediminias Matulis
Author: Salah Mansour ORCID iD
Author: Nicholas J. Pumphrey
Author: Nikolai Lissin
Author: Peter M. Villiger
Author: Bent Jakobsen
Author: Jose D. Faraldo-Gomez
Author: Stephan D. Gadola

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