<scp>CD</scp>1d protein structure determines species‐selective antigenicity of isoglobotrihexosylceramide (i<scp>G</scp>b3) to invariant <scp>NKT</scp> cells

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<jats:p>Isoglobotrihexosylceramide (i<jats:styled-content style="fixed-case">G</jats:styled-content>b3) has been identified as a potent <jats:styled-content style="fixed-case">CD</jats:styled-content>1d‐presented self‐antigen for mouse invariant natural killer T (i<jats:styled-content style="fixed-case">NKT</jats:styled-content>) cells. The role of i<jats:styled-content style="fixed-case">G</jats:styled-content>b3 in humans remains unresolved, however, as there have been conflicting reports about i<jats:styled-content style="fixed-case">G</jats:styled-content>b3‐dependent human i<jats:styled-content style="fixed-case">NKT</jats:styled-content>‐cell activation, and humans lack i<jats:styled-content style="fixed-case">G</jats:styled-content>b3 synthase, a key enzyme for i<jats:styled-content style="fixed-case">G</jats:styled-content>b3 synthesis. Given the importance of human immune responses, we conducted a human–mouse cross‐species analysis of i<jats:styled-content style="fixed-case">NKT</jats:styled-content>‐cell activation by i<jats:styled-content style="fixed-case">G</jats:styled-content>b3‐<jats:styled-content style="fixed-case">CD</jats:styled-content>1d. Here we show that human and mouse i<jats:styled-content style="fixed-case">NKT</jats:styled-content> cells were both able to recognise i<jats:styled-content style="fixed-case">G</jats:styled-content>b3 presented by mouse <jats:styled-content style="fixed-case">CD</jats:styled-content>1d (m<jats:styled-content style="fixed-case">CD</jats:styled-content>1d), but not human <jats:styled-content style="fixed-case">CD</jats:styled-content>1d (h<jats:styled-content style="fixed-case">CD</jats:styled-content>1d), as i<jats:styled-content style="fixed-case">G</jats:styled-content>b3‐h<jats:styled-content style="fixed-case">CD</jats:styled-content>1d was unable to support cognate interactions with the i<jats:styled-content style="fixed-case">NKT</jats:styled-content>‐cell <jats:styled-content style="fixed-case">TCR</jats:styled-content>s tested in this study. The structural basis for this discrepancy was identified as a single amino acid variation between h<jats:styled-content style="fixed-case">CD</jats:styled-content>1d and m<jats:styled-content style="fixed-case">CD</jats:styled-content>1d, a glycine‐to‐tryptophan modification within the α2‐helix that prevents flattening of the i<jats:styled-content style="fixed-case">G</jats:styled-content>b3 headgroup upon <jats:styled-content style="fixed-case">TCR</jats:styled-content> ligation. Mutation of the human residue, <jats:styled-content style="fixed-case">T</jats:styled-content>rp153, to the mouse ortholog, <jats:styled-content style="fixed-case">G</jats:styled-content>ly155, therefore allowed i<jats:styled-content style="fixed-case">G</jats:styled-content>b3‐h<jats:styled-content style="fixed-case">CD</jats:styled-content>1d to stimulate human i<jats:styled-content style="fixed-case">NKT</jats:styled-content> cells. In conclusion, our data indicate that i<jats:styled-content style="fixed-case">G</jats:styled-content>b3 is unlikely to be a major antigen in human i<jats:styled-content style="fixed-case">NKT</jats:styled-content>‐cell biology.</jats:p>

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