Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors

Area of Science:

• Immunology
• Cellular and Molecular Immunology
• NK Cell Biology

Background:

• Natural killer (NK) cells are crucial for innate immunity, recognizing and eliminating target cells.
• NK cell activity is regulated by a balance of activating and inhibitory receptors, including KIR and CD94:NKG2.
• Killer cell immunoglobulin-like receptors (KIR) and CD94:NKG2 receptors interact with Human Leukocyte Antigen (HLA) class I molecules.

Purpose of the Study:

• To investigate the relationship between KIR and CD94:NKG2 receptor expression on NK cell clones and their inhibitory responses.
• To determine how genetic differences in HLA class I and KIR genes between individuals influence NK cell recognition and cytotoxicity.

Main Methods:

• Isolation and cloning of over 100 NK cell clones from two unrelated blood donors.
• Analysis of KIR and CD94:NKG2 receptor expression on individual NK cell clones.
• Assessment of NK cell clone inhibition by autologous HLA class I allotypes.

Main Results:

• Over 98% of NK cell clones were inhibited by autologous HLA class I, with 100% inhibition when multiple allotypes were combined.
• The pattern of NK cell inhibition correlated with the expression of specific inhibitory receptors (KIR or CD94:NKG2a).
• Donor 1, with multiple KIR ligands, predominantly used KIR, while Donor 2, with a single KIR ligand, primarily used CD94:NKG2a, leading to donor-specific NK cell cytotoxicity.

Conclusions:

• Individual differences in HLA class I ligands and KIR genes shape NK cell receptor repertoire and function.
• The specific inhibitory receptor used by NK cells (KIR vs. CD94:NKG2a) is dictated by ligand availability, influencing inter-individual NK cell responses.
• This study highlights the genetic basis for NK cell tolerance and potential for allogeneic NK cell-mediated rejection.