The Antigen-Specific Response of NK Cells to SARS-CoV-2 Correlates With KIR2DS4 Expression
Language English Country United States Media print
Document type Journal Article
Grant support
This research was funded by the Russian Science Foundation grant No 22-15-00503. Experiments using MagPix were performed at the Sirius University of Science and Technology and supported by the Ministry of Science and Higher Education of the Russian Federation (Agreement 075-10-2021-093).
PubMed
39540437
DOI
10.1002/jmv.70057
Knihovny.cz E-resources
- Keywords
- KIR2DS4, NK cells, SARS‐CoV‐2, antigen‐specific NK cells,
- MeSH
- Lymphocyte Activation MeSH
- Killer Cells, Natural * immunology MeSH
- COVID-19 * immunology MeSH
- Cell Degranulation MeSH
- Adult MeSH
- Immunoglobulin G MeSH
- Immunologic Memory MeSH
- Interferon-gamma * immunology metabolism MeSH
- Middle Aged MeSH
- Humans MeSH
- Antibodies, Viral blood immunology MeSH
- Receptors, KIR genetics metabolism MeSH
- SARS-CoV-2 * immunology MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Immunoglobulin G MeSH
- Interferon-gamma * MeSH
- Antibodies, Viral MeSH
- Receptors, KIR MeSH
Natural killer (NK) cells play a pivotal role in the immune response against viral infections, including SARS-CoV-2. However, our understanding of memory NK cell responses in the context of SARS-CoV-2 remains limited. To address this, we investigated the memory-like response of NK cells to SARS-CoV-2 peptides, presented by autologous cells. Blood samples from 45 donors underwent analysis for SARS-CoV-2 IgG antibodies, categorizing them into four groups based on the antibody kind and level. NK cells from SARS-CoV-2-experienced donors demonstrated enhanced degranulation and activation levels, IFNγ production and proliferative potential in response to SARS-CoV-2 peptides. Investigation of highly proliferating NK cells demonstrated the formation of distinct clusters depending on the SARS-CoV-2 peptide supplementation and the donor group. RNA sequencing revealed differential gene expression patterns, highlighting metabolism, protein transport, and immune response genes. Notably, KIR2DS4 expression correlated with enhanced IFNγ production, degranulation and proliferation levels, suggesting a role in SARS-CoV-2 recognition. Collectively, these findings provide detailed insights into antigen-specific NK cell responses to SARS-CoV-2 peptides, indicating potential mechanisms underlying NK cell activation in antiviral immunity.
Central European Institute of Technology Masaryk University Brno Czech Republic
Department Bioinformatics Abu Dhabi Stem Cell Center Al Muntazah Abu Dhabi United Arab Emirates
See more in PubMed
S. Sivori, P. Vacca, G. Del Zotto, E. Munari, M. C. Mingari, and L. Moretta, “Human Nk Cells: Surface Receptors, Inhibitory Checkpoints, and Translational Applications,” Cellular & Molecular Immunology 16, no. 5 (2019): 430–441, https://doi.org/10.1038/s41423-019-0206-4.
M. Vales‐Gomez, “Kinetics and Peptide Dependency of the Binding of the Inhibitory Nk Receptor CD94/NKG2‐A and the Activating Receptor CD94/NKG2‐C to HLA‐E,” The EMBO Journal 18, no. 15 (1999): 4250–4260, https://doi.org/10.1093/EMBOJ/18.15.4250.
C. A. Stewart, F. Laugier‐Anfossi, F. Vély, et al., “Recognition of Peptide–MHC Class I Complexes by Activating Killer Immunoglobulin‐Like Receptors,” Proceedings of the National Academy of Sciences 102, no. 37 (2005): 13224–13229, https://doi.org/10.1073/PNAS.0503594102.
A. D. Colantonio, B. N. Bimber, W. J. Neidermyer, et al., “KIR Polymorphisms Modulate Peptide‐Dependent Binding to an MHC Class I Ligand with a Bw6 Motif,” PLoS Pathogens 7, no. 3 (2011): e1001316, https://doi.org/10.1371/JOURNAL.PPAT.1001316.
L. Fadda, G. Borhis, P. Ahmed, et al., “Peptide Antagonism as a Mechanism for Nk Cell Activation,” Proceedings of the National Academy of Sciences 107, no. 22 (2010): 10160–10165, https://doi.org/10.1073/PNAS.0913745107/-/DCSUPPLEMENTAL.
Q. Hammer, T. Rückert, and C. Romagnani, “Natural Killer Cell Specificity for Viral Infections,” Nature Immunology 19, no. 8 (2018): 800–808, https://doi.org/10.1038/s41590-018-0163-6.
M. M. Naiyer, S. A. Cassidy, A. Magri, et al., “KIR2DS2 Recognizes Conserved Peptides Derived From Viral Helicases in the Context of HLA‐C,” Science Immunology 2, no. 15 (2017): 5296, https://doi.org/10.1126/SCIIMMUNOL.AAL5296.
M. J. W. Sim, S. Rajagopalan, D. M. Altmann, R. J. Boyton, P. D. Sun, and E. O. Long, “Human Nk Cell Receptor KIR2DS4 Detects a Conserved Bacterial Epitope Presented by HLA‐C,” Proceedings of the National Academy of Sciences 116, no. 26 (2019): 12964–12973, https://doi.org/10.1073/PNAS.1903781116/-/DCSUPPLEMENTAL.
M. Gumá, M. Budt, A. Sáez, et al., “Expansion of CD94/NKG2C+ Nk Cells in Response to Human Cytomegalovirus‐Infected Fibroblasts,” Blood 107, no. 9 (2006): 3624–3631, https://doi.org/10.1182/BLOOD-2005-09-3682.
Z. Wu, C. Sinzger, G. Frascaroli, et al., “Human Cytomegalovirus‐Induced NKG2Chi CD57hi Natural Killer Cells Are Effectors Dependent on Humoral Antiviral Immunity,” Journal of Virology 87, no. 13 (2013): 7717–7725, https://doi.org/10.1128/JVI.01096-13.
A. Rölle, M. Meyer, S. Calderazzo, D. Jäger, and F. Momburg, “Distinct HLA‐E Peptide Complexes Modify Antibody‐Driven Effector Functions of Adaptive NK Cells,” Cell Reports 24, no. 8 (2018): 1967–1976.e4, https://doi.org/10.1016/j.celrep.2018.07.069.
Q. Hammer, T. Rückert, E. M. Borst, et al., “Peptide‐Specific Recognition of Human Cytomegalovirus Strains Controls Adaptive Natural Killer Cells,” Nature Immunology 19, no. 5 (2018): 453–463, https://doi.org/10.1038/S41590-018-0082-6.
M. O. Ustiuzhanina, M. A. Streltsova, N. D. Timofeev, M. A. Kryukov, D. M. Chudakov, and E. I. Kovalenko, “Autologous T‐Cell‐Free Antigen Presentation System Unveils hCMV‐Specific Nk Cell Response,” Cells 13, no. 6 (2024): 530, https://doi.org/10.3390/CELLS13060530.
M. J. Lee and C. A. Blish, “Defining the Role of Natural Killer Cells in COVID‐19,” Nature Immunology 24, no. 10 (2023): 1628–1638, https://doi.org/10.1038/S41590-023-01560-8.
C. Maucourant, I. Filipovic, A. Ponzetta, et al., “Natural Killer Cell Immunotypes Related to COVID‐19 Disease Severity,” Science Immunology 5, no. 50 (2020): 6832, https://doi.org/10.1126/SCIIMMUNOL.ABD6832.
C. Di Vito, F. Calcaterra, N. Coianiz, et al., “Natural Killer Cells in SARS‐CoV‐2 Infection: Pathophysiology and Therapeutic Implications,” Frontiers in Immunology 13 (2022): 888248, https://doi.org/10.3389/FIMMU.2022.888248.
M. O. Ustiuzhanina, J. D. Vavilova, A. A. Boyko, et al., “Coordinated Loss and Acquisition of Nk Cell Surface Markers Accompanied by Generalized Cytokine Dysregulation in COVID‐19,” International Journal of Molecular Sciences 24, no. 3 (2023): 1996, https://doi.org/10.3390/IJMS24031996.
S. Varchetta, D. Mele, B. Oliviero, et al., “Unique Immunological Profile in Patients With COVID‐19,” Cellular & Molecular Immunology 18, no. 3 (2021): 604–612, https://doi.org/10.1038/S41423-020-00557-9.
C. Guo, M. Wu, B. Huang, et al., “Single‐Cell Transcriptomics Reveal a Unique Memory‐Like NK Cell Subset That Accumulates With Ageing and Correlates With Disease Severity in COVID‐19,” Genome Medicine 14, no. 1 (2022): 46, https://doi.org/10.1186/S13073-022-01049-3.
A. A. Boyko, M. O. Ustiuzhanina, J. D. Vavilova, et al., “Phenotypic Changes in T and NK Cells Induced by Sputnik V Vaccination,” Vaccines 11, no. 6 (2023): 1047, https://doi.org/10.3390/VACCINES11061047/S1.
T. Takano, M. Morikawa, Y. Adachi, et al., “Distinct Immune Cell Dynamics Correlate With the Immunogenicity and Reactogenicity of SARS‐CoV‐2 mRNA Vaccine,” Cell reports. Medicine 3, no. 5 (2022): 100631, https://doi.org/10.1016/J.XCRM.2022.100631.
C. Li, A. Lee, L. Grigoryan, et al., “Mechanisms of Innate and Adaptive Immunity to the Pfizer‐BioNTech BNT162b2 Vaccine,” Nature Immunology 23, no. 4 (2022): 543–555, https://doi.org/10.1038/S41590-022-01163-9.
M. Saresella, F. Piancone, I. Marventano, et al., “Innate Immune Responses to Three Doses of the BNT162b2 mRNA SARS‐CoV‐2 Vaccine,” Frontiers in Immunology 13 (2022): 947320, https://doi.org/10.3389/FIMMU.2022.947320/BIBTEX.
A. Cuapio, C. Boulouis, I. Filipovic, et al., “NK Cell Frequencies, Function and Correlates to Vaccine Outcome in BNT162b2 mRNA anti‐SARS‐CoV‐2 Vaccinated Healthy and Immunocompromised Individuals,” Molecular Medicine 28, no. 1 (2022): 20, https://doi.org/10.1186/S10020-022-00443-2/FIGURES/4.
D. Mele, S. Ottolini, A. Lombardi, et al., “Long‐Term Dynamics of Natural Killer Cells in Response to SARS‐CoV‐2 Vaccination: Persistently Enhanced Activity Postvaccination,” Journal of Medical Virology 96, no. 4 (2024): e29585, https://doi.org/10.1002/JMV.29585.
L. Herrera, M. Martin‐Inaraja, S. Santos, et al., “Identifying SARS‐CoV‐2 “Memory” NK Cells From COVID‐19 Convalescent Donors for Adoptive Cell Therapy,” Immunology 165, no. 2 (2022): 234–249, https://doi.org/10.1111/IMM.13432.
A. E. Siniavin, M. A. Streltsova, M. A. Nikiforova, et al., “Snake Venom Phospholipase A2s Exhibit Strong Virucidal Activity Against SARS‐CoV‐2 and Inhibit the Viral Spike Glycoprotein Interaction with ACE2,” Cellular and Molecular Life Sciences 78, no. 23 (2021): 7777–7794, https://doi.org/10.1007/S00018-021-03985-6/FIGURES/7.
A. E. Siniavin, V. A. Gushchin, N. S. Shastina, et al., “New Conjugates Based on N4‐hydroxycytidine with More Potent Antiviral Efficacy in Vitro Than EIDD‐2801 Against SARS‐CoV‐2 and Other Human Coronaviruses,” Antiviral Research 225 (2024): 105871, https://doi.org/10.1016/J.ANTIVIRAL.2024.105871.
S. L. Heatley, G. Pietra, J. Lin, et al., “Polymorphism in Human Cytomegalovirus UL40 Impacts on Recognition of Human Leukocyte Antigen‐E (HLA‐E) by Natural Killer Cells,” Journal of Biological Chemistry 288, no. 12 (2013): 8679–8690, https://doi.org/10.1074/JBC.M112.409672.
R. Patro, G. Duggal, M. I. Love, R. A. Irizarry, and C. Kingsford, “Salmon Provides Fast and Bias‐Aware Quantification of Transcript Expression Using Dual‐Phase Inference,” Nature Methods 14, no. 4 (2017): 417–419, https://doi.org/10.1038/NMETH.4197.
M. I. Love, W. Huber, and S. Anders, “Moderated Estimation of Fold Change and Dispersion for RNA‐seq Data With DESeq. 2,” Genome Biology 15, no. 12 (2014): 550, https://doi.org/10.1186/S13059-014-0550-8/FIGURES/9.
KIR2DS4 Human qPCR Primer Pair (NM_012314) – HP210275 | OriGene., accessed September 30, 2024, https://www.origene.com/catalog/gene-expression/qpcr-primer-pairs/hp210275/kir2ds4-human-qpcr-primer-pair-nm_012314.
N. Huot, C. Planchais, P. Rosenbaum, et al., “SARS‐CoV‐2 Viral Persistence in Lung Alveolar Macrophages Is Controlled by IFN‐γ and NK Cells,” Nature Immunology 24, no. 12 (2023): 2068–2079, https://doi.org/10.1038/s41590-023-01661-4.
C. Di Vito, F. Calcaterra, N. Coianiz, et al., “Natural Killer Cells in SARS‐CoV‐2 Infection: Pathophysiology and Therapeutic Implications,” Frontiers in Immunology 13 (2022): 888248, https://doi.org/10.3389/FIMMU.2022.888248/BIBTEX.
K. Dybkaer, J. Iqbal, G. Zhou, et al., “Genome Wide Transcriptional Analysis of Resting and IL2 Activated Human Natural Killer Cells: Gene Expression Signatures Indicative of Novel Molecular Signaling Pathways,” BMC Genomics 8 (2007): 230, https://doi.org/10.1186/1471-2164-8-230.
A. Cui, T. Huang, S. Li, et al., “Dictionary of Immune Responses to Cytokines at Single‐Cell Resolution,” Nature 625, no. 7994 (2024): 377–384, https://doi.org/10.1038/s41586-023-06816-9.
Y. S. Lee, S. H. Hong, H. J. Park, et al., “Peptides Derived From S and N Proteins of Severe Acute Respiratory Syndrome Coronavirus 2 Induce T Cell Responses: A Proof of Concept for T Cell Vaccines,” Frontiers in Microbiology 12 (2021): 732450, https://doi.org/10.3389/FMICB.2021.732450/BIBTEX.
J. H. Evans, A. Horowitz, M. Mehrabi, et al., “A Distinct Subset of Human NK Cells Expressing HLA‐Dr Expand in Response to IL‐2 and Can Aid Immune Responses to BCG,” European Journal of Immunology 41, no. 7 (2011): 1924–1933, https://doi.org/10.1002/EJI.201041180.
S. Charrin, S. Jouannet, C. Boucheix, and E. Rubinstein, “Tetraspanins at a Glance,” Journal of Cell Science 127, no. Pt 17 (2014): 3641–3648, https://doi.org/10.1242/JCS.154906.
A. Hikita, N. Tanaka, S. Yamane, et al., “Involvement of a Disintegrin and Metalloproteinase 10 and 17 in Shedding of Tumor Necrosis Factor‐Α,” Biochemistry and Cell Biology 87, no. 4 (2009): 581–593, https://doi.org/10.1139/O09-015.
J. Palmowski, S. Kohnhorst, P. Bauer, et al., “T‐Cell‐Derived TNF‐α and a Cluster of Immunological Parameters From Plasma Allow a Separation Between SARS‐CoV‐2 Convalescent Versus Vaccinated Elite Athletes,” Frontiers in Physiology 14 (2023): 1203983, https://doi.org/10.3389/FPHYS.2023.1203983/BIBTEX.
T. Rückert, C. A. Lareau, M. F. Mashreghi, L. S. Ludwig, and C. Romagnani, “Clonal Expansion and Epigenetic Inheritance of Long‐Lasting NK Cell Memory,” Nature Immunology 23, no. 11 (2022): 1551–1563, https://doi.org/10.1038/s41590-022-01327-7.
A. J. Wilk, M. J. Lee, B. Wei, et al., “Multi‐Omic Profiling Reveals Widespread Dysregulation of Innate Immunity and Hematopoiesis in COVID‐19,” Journal of Experimental Medicine 218, no. 8 (2021): e20210582, https://doi.org/10.1084/JEM.20210582.
G. Leem, S. Cheon, H. Lee, et al., “Abnormality in the NK‐Cell Population Is Prolonged in Severe COVID‐19 Patients,” Journal of Allergy and Clinical Immunology 148, no. 4 (2021): 996–1006.e18, https://doi.org/10.1016/J.JACI.2021.07.022.
J. Siemaszko, A. Marzec‐Przyszlak, and K. Bogunia‐Kubik, “Activating NKG2C Receptor: Functional Characteristics and Current Strategies in Clinical Applications,” Archivum Immunologiae et Therapiae Experimentalis 71, no. 1 (2023): 9, https://doi.org/10.1007/S00005-023-00674-Z.
P. Höglund and P. Brodin, “Current Perspectives of Natural Killer Cell Education by MHC Class I Molecules,” Nature Reviews Immunology 10, no. 10 (2010): 724–734, https://doi.org/10.1038/nri2835.
J. E. Boudreau, X. R. Liu, Z. Zhao, et al., “Cell‐Extrinsic MHC Class I Molecule Engagement Augments Human NK Cell Education Programmed by Cell‐Intrinsic MHC Class I,” Immunity 45, no. 2 (2016): 280–291, https://doi.org/10.1016/J.IMMUNI.2016.07.005.
H. Kared, S. Martelli, T. P. Ng, S. L. F. Pender, and A. Larbi, “CD57 in Human Natural Killer Cells and T‐Lymphocytes,” Cancer Immunology, Immunotherapy 65, no. 4 (2016): 441–452, https://doi.org/10.1007/s00262-016-1803-z.
R. Kaur, T. Tada, and N. R. Landau, “Restriction of SARS‐CoV‐2 Replication by Receptor Transporter Protein 4 (RTP4),” mBio 14, no. 4 (2023): 0109023, https://doi.org/10.1128/MBIO.01090-23/SUPPL_FILE/MBIO.01090-23-S0009.DOCX.
A. F. Rendeiro, J. Casano, C. K. Vorkas, et al., “Profiling of Immune Dysfunction in COVID‐19 Patients Allows Early Prediction of Disease Progression,” Life Science Alliance 4, no. 2 (2021): e202000955, https://doi.org/10.26508/LSA.202000955.
