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

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)

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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Contributors

Author: Salah Mansour

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