Polygenic polymorphism is associated with NKG2A repertoire and influences lymphocyte phenotype and function.

CD94/NKG2A is a heterodimeric receptor commonly found on NK and T cells, and interaction with its ligand HLA-E on adjacent cells leads to inhibitory signaling and cell suppression. We have identified several KLRC1 (NKG2A) single nucleotide polymorphisms (SNPs) that are associated with NKG2A expression on NK cells, CD8+ T cells, and V9/V2+ T cells. Additionally, due to strong linkage disequilibrium, polymorphisms in KLRC2 (NKG2C) and KLRK1 (NKG2D) are also associated with NKG2A surface density and frequency. NKG2A surface expression correlates with single cell NK responsiveness, and NKG2A+ NK cell frequency is associated with total NK repertoire response and inhibitability, making identification of SNPs responsible for expression and frequency important for predicting innate immune response. As HLA-E expression is dependent on HLA class I signal peptide, we analyzed the relationship between peptide abundance and HLA-E expression levels. Our findings reveal a strong association between peptide availability and HLA-E expression. We identified the HLA-C KIR ligand epitope as a predictive marker for HLA-ABC expression, with the HLA-C1 epitope associated with high HLA-E expression, and the HLA-C2 epitope associated with low HLA-E expression. The relationship between HLA-C epitopes and HLA-E expression is independent of HLA-E allotypes and HLA-B leader peptide. While HLA-E expression shows no significant influence on NKG2A-mediated NK education, it does affect NK cell inhibition. In summary, these findings underscore the importance of NKG2A SNPs and HLA-C epitopes as predictive markers of NK cell phenotype and function and should be evaluated as prognostic markers for diseases expressing high levels of HLA-E.

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