Natural variations at position 93 of the invariant Vα24-Jα18 α chain of human iNKT-cell TCRs strongly impact on CD1d binding

Sanderson, Joseph P; Waldburger-Hauri, Kathrin; Garzón, Diana; Matulis, Gediminas; Mansour, Salah; Pumphrey, Nicholas J; Lissin, Nikolai; Villiger, Peter M; Jakobsen, Bent; Faraldo-Gómez, José D; Gadola, Stephan D (2012). Natural variations at position 93 of the invariant Vα24-Jα18 α chain of human iNKT-cell TCRs strongly impact on CD1d binding. European journal of immunology, 42(1), pp. 248-55. Weinheim: Wiley-VCH 10.1002/eji.201141956

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Human invariant natural killer T (NKT) cell TCRs bind to CD1d via an "invariant" Vα24-Jα18 chain (iNKTα) paired to semi-invariant Vβ11 chains (iNKTβ). Single-amino acid variations at position 93 (p93) of iNKTα, immediately upstream of the "invariant" CDR3α 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 CDR3α loop. By generating recombinant refolded iNKT-cell TCRs, we show that natural single-nucleotide variations in iNKTα, 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 α-galactosylceramide antigens KRN7000 or OCH, or the endogenous glycolipid β-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 CDR3α loop.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Rheumatology and Immunology
UniBE Contributor:	Villiger, Peter Matthias
ISSN:	0014-2980
Publisher:	Wiley-VCH
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:23
Last Modified:	05 Dec 2022 14:06
Publisher DOI:	10.1002/eji.201141956
PubMed ID:	21956730
Web of Science ID:	000298596600027
URI:	https://boris.unibe.ch/id/eprint/7951 (FactScience: 213339)