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

Sep 30, 2011European journal of immunology

Natural differences at position 93 in a key part of human iNKT-cell receptors strongly affect their binding to CD1d

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Abstract

Single-nucleotide variations at position 93 of the invariant NKT cell TCR can lead to up to 28-fold differences in binding affinity to CD1d.

Variations at position 93 in the invariant TCR influence the conformation of the CDR3α loop, affecting CD1d binding.
The presence of serine, threonine, asparagine, or isoleucine at position 93 alters the affinity for CD1d.
The strongest CD1d binding was observed with the serine-containing variant, which is the most common in human iNKT cells.
Binding studies demonstrated that these variants affect autoreactive recognition of endogenous lipids.
Molecular dynamics modeling supports the hypothesis that position 93 influences the structural configuration of the TCR.

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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.

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