NKT TCR recognition of CD1d-α-C-galactosylceramide

Area of Science:

• Immunology
• Structural Biology
• Glycobiology

Background:

• Natural killer T (NKT) cells are crucial immune cells recognizing CD1d-restricted glycolipid antigens.
• Alpha-galactosylceramide (α-GalCer) is a prototypic NKT cell antigen.
• Modified analogs like alpha-C-GalCer (α-C-GalCer) with carbon-based glycosidic linkages are of interest for potentially prolonged, Th1-biased immune responses.

Purpose of the Study:

• To investigate the activation of spleen NKT cells by α-C-GalCer and related C-glycoside ligands.
• To determine the affinity of specific NKT cell T cell receptors (TCRs) for CD1d-α-C-GalCer complexes compared to CD1d-α-GalCer.
• To elucidate the structural basis for differences in NKT cell activation and TCR affinity.

Main Methods:

• Activation assays of spleen NKT cells.
• Analysis of NKT TCR affinity for CD1d-glycolipid complexes.
• Crystal structure determination of the Vβ8.2 NKT TCR-CD1d-α-C-GalCer complex.

Main Results:

• Activation of NKT cells by α-C-GalCer and related C-glycosides was weaker than by α-GalCer.
• The affinity of Vβ8.2 and Vβ7 NKT TCRs for CD1d-α-C-GalCer was approximately 10-fold lower than for CD1d-α-GalCer.
• The crystal structure of the Vβ8.2 NKT TCR-CD1d-α-C-GalCer complex was similar to the CD1d-α-GalCer complex, with subtle interface differences explaining the lower affinity.

Conclusions:

• Altered glycolipid ligands, such as α-C-GalCer, can elicit distinct immune responses from CD1d-restricted NKT cells.
• Despite lower affinity, the TCR-docking topology remains similar between α-C-GalCer and α-GalCer interactions.
• Structural insights explain the reduced affinity of NKT TCRs for C-glycoside analogs, impacting immune response modulation.