Innate-like control of human iNKT cell autoreactivity via the hypervariable CDR3beta loop

Area of Science:

• Immunology
• Cellular Biology

Background:

• Invariant Natural Killer T (iNKT) cells are lymphocytes vital for immune defense and tolerance.
• iNKT cells recognize lipid antigens presented by CD1d molecules via a conserved T cell receptor (TCR).
• The CDR3beta loop of the iNKT TCR is hypervariable, yet its role in CD1d binding and antigen recognition remains debated.

Purpose of the Study:

• To investigate the impact of the CDR3beta loop on human iNKT cell TCR affinity to CD1d.
• To determine if CDR3beta influences iNKT cell autoreactivity and responses to different CD1d-presented lipids.

Main Methods:

• Surface plasmon resonance was used to measure the affinity of recombinant iNKT TCRs to various CD1d-ligand complexes.
• CD1d-tetramer binding assays were performed using iNKT cell subsets with different autoreactive functions.
• Analysis of iNKT TCR affinity was correlated with functional responses to CD1d presenting diverse glycolipid antigens.

Main Results:

• Human iNKT cells exhibit a range of TCR affinities to CD1d, linked to their autoreactive functions.
• The CDR3beta loop sequence significantly modulates iNKT TCR affinity for CD1d, irrespective of the presented ligand.
• iNKT cell subsets segregated in their binding to CD1d-tetramers loaded with partial agonists and endogenous beta-glycosylceramides.

Conclusions:

• The CDR3beta loop plays a critical role in determining human iNKT TCR affinity to CD1d.
• This CDR3beta-mediated affinity tuning establishes an inherent functional hierarchy within human iNKT cells.
• The findings provide a molecular basis for understanding iNKT cell functional diversity and autoreactivity.