Polygenic polymorphism is associated with NKG2A repertoire and influences lymphocyte phenotype and function Journal Article
| Authors: | Le Luduec, J. B.; Kontopoulos, T.; Panjwani, M. K.; Sottile, R.; Liu, H.; Schäfer, G.; Massalski, C.; Lange, V.; Hsu, K. C. |
| Article Title: | Polygenic polymorphism is associated with NKG2A repertoire and influences lymphocyte phenotype and function |
| 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 Vy9/VS2' 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. |
| Keywords: | methylation; dna; receptor; leukemia relapse; t-cells; natural-killer-cells; surface expression; nk cells; e expression; inhibitory; hla class-i; impaired function |
| Journal Title: | Blood Advances |
| Volume: | 8 |
| Issue: | 20 |
| ISSN: | 2473-9529 |
| Publisher: | American Society of Hematology |
| Date Published: | 2024-10-22 |
| Start Page: | 5382 |
| End Page: | 5399 |
| Language: | English |
| ACCESSION: | WOS:001335802400001 |
| DOI: | 10.1182/bloodadvances.2024013508 |
| PROVIDER: | wos |
| PUBMED: | 39158076 |
| PMCID: | PMC11568789 |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Jean-Benoît Le Luduec -- Source: Wos |
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