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Updated: Jun 16, 2025
T and B Cell Receptor Immune Repertoire Analysis using Next-generation Sequencing
Published on: January 12, 2021
Polygenic polymorphism is associated with NKG2A repertoire and influences lymphocyte phenotype and function
Jean-Benoît Le Luduec1, Theodota Kontopoulos1, M Kazim Panjwani1
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.
Insights
Single nucleotide polymorphisms (SNPs) in killer cell lectin-like receptor C1 (NKG2A) impact NKG2A expression and NK cell function. HLA-C epitopes also predict HLA-E expression, influencing NK cell responses and disease prognosis.
Area of Science:
- Immunology
- Cellular and Molecular Immunology
- Genetics and Genomics
Background:
- The CD94/NKG2A receptor complex on NK and T cells mediates inhibitory signaling upon binding HLA-E.
- NKG2A expression levels influence NK cell responsiveness and overall immune repertoire function.
- HLA-E expression is regulated by HLA class I signal peptides and peptide availability.
Purpose of the Study:
- To identify single nucleotide polymorphisms (SNPs) associated with NKG2A expression on immune cells.
- To investigate the relationship between peptide abundance and HLA-E expression.
- To determine the predictive value of NKG2A SNPs and HLA-C epitopes for NK cell phenotype and function.
Main Methods:
- Analysis of killer cell lectin-like receptor C1 (KLR C1) SNPs associated with NKG2A expression.
- Investigation of linkage disequilibrium between KLR C1, KLRC2 (NKG2C), and KLRK1 (NKG2D) polymorphisms.
- Correlation of NKG2A surface expression with NK cell responsiveness and frequency.
- Analysis of the relationship between peptide availability and HLA-E expression levels.
- Identification of HLA-C epitopes as predictive markers for HLA-ABC and HLA-E expression.
Main Results:
- Several KLR C1 (NKG2A) SNPs were associated with NKG2A expression on NK, CD8+, and Vγ9/Vδ2+ T cells.
- Polymorphisms in KLRC2 (NKG2C) and KLRK1 (NKG2D) are linked to NKG2A surface density and frequency.
- Peptide availability strongly correlates with HLA-E expression levels.
- HLA-C1 epitopes are associated with high HLA-E expression, while HLA-C2 epitopes are linked to low HLA-E expression, independent of HLA-E allotypes.
- HLA-E expression impacts NK cell inhibition but not NKG2A-mediated NK education.
Conclusions:
- NKG2A SNPs and HLA-C epitopes serve as important predictive markers for NK cell phenotype and function.
- These genetic factors influence innate immune response and NK cell inhibitability.
- NKG2A SNPs and HLA-C epitopes warrant evaluation as prognostic markers for diseases with high HLA-E expression.
Abstract:
CD94/NKG2A is a heterodimeric receptor commonly found on natural killer (NK) and T cells, and its interaction with its ligand HLA-E on adjacent cells leads to inhibitory signaling and cell suppression. We have identified several killer cell lectin-like receptor (KLR)C1 (NKG2A) single nucleotide polymorphisms (SNPs) that are associated with NKG2A expression on NK cells, CD8+ T cells, and Vγ9/Vδ2+ 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 the identification of SNPs responsible for expression and frequency important for predicting the innate immune response. Because HLA-E expression is dependent on HLA class I signal peptides, we analyzed the relationship between peptide abundance and HLA-E expression levels. Our findings revealed a strong association between peptide availability and HLA-E expression. We identified the HLA-C killer immunoglobulin-like receptor 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 was independent of HLA-E allotypes and HLA-B leader peptides. Although HLA-E expression showed no significant influence on NKG2A-mediated NK education, it did 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 that express high levels of HLA-E.
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