Lysophospholipid presentation by CD1d and recognition by a human Natural Killer T-cell receptor

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• Invariant Natural Killer T (iNKT) cells are crucial immune cells utilizing restricted T cell receptors (TCRs) to survey lipid antigens presented by CD1d molecules.
• Understanding the presentation of various lipids, including lysophospholipids, by CD1d is vital for deciphering iNKT cell activation pathways.

Purpose of the Study:

• To investigate the presentation of lysophosphatidylcholine (LPC) by human CD1d molecules.
• To characterize the recognition of the CD1d-LPC complex by a specific LPC-recognizing iNKT TCR.

Main Methods:

• Structural analysis of human CD1d presenting LPC.
• Biochemical studies of iNKT TCR binding to the CD1d-LPC complex.
• Detailed examination of conformational changes in CD1d and TCR interactions.

Main Results:

• Human CD1d presents LPC with an altered conformation, featuring a shifted α1 helix and an open A' pocket compared to CD1d-glycolipid complexes.
• iNKT TCR binding induces a 7-Å displacement of the LPC headgroup, stabilizing the CD1d-LPC complex in a closed conformation.
• The iNKT TCR-CD1d-LPC interaction is anchored by the CDR3α loop, with other CDR loops repositioned due to TCR sequence variations.

Conclusions:

• Lysophospholipids are presented by human CD1d through distinct structural mechanisms.
• The recognition of CD1d-lysophospholipid complexes by iNKT cells is mediated by specific TCR structural adaptations.
• These findings elucidate the molecular basis for recognition of certain lysophospholipids by a subset of human iNKT cells.