Coordination of NK cell markers expression and IgG response in hCMV infection

Human cytomegalovirus (hCMV) is a prevalent virus that affects a large proportion of the population worldwide. Natural Killer (NK) cells are essential immune cells that play a crucial role in controlling hCMV infection. Despite the wide spread of hCMV infection, there is still not enough data related to the association between innate and adaptive immunity. This study investigated the coordination between some of the NK cell markers expression and humoral immune response during hCMV infection. Thirty-three samples obtained from different healthy donors were investigated. The anti-hCMV IgG antibody titer was measured in serum samples, and expression of NKG2C, HLA-DR, CD57, KIR2DL2/DL3, and KIR2DL1 were analyzed in CD56⁺CD3^- cells in PBMC samples by flow cytometry. To evaluate the dependence of proportions of different NK cell subsets on IgG titers, cluster analysis was first performed on all the obtained data, resulting in the identification of four main clusters. The identified clusters demonstrated a dependence on the levels of hCMV antibodies, according to which clusters corresponding to seronegative and low-positive were grouped. The results confirmed that hCMV infection leads to an expansion of NK cell populations expressing the NKG2C marker, which correlates with higher levels of IgG response to hCMV. Besides, we identified increased HLA-DR⁺ and decreased of KIR2DL1⁺ NK cells proportions in the middle anti-CMV-IgG level group compared to samples obtained from seronegative and low-positive donors. Moreover, the statistically significant negative correlation was found between KIR2DL1⁺NK cell percentage and anti-CMV IgG antibody titer, while the positive correlation between HLA-DR⁺NK cell proportion and the IgG level was noticed only without the cluster corresponded to high level of anti-hCMV IgG. In this cohort, we did not find any association between KIR2DL3 and CD57 expression in NK cells and levels of IgG response to hCMV. This may indicate that different subsets of NK cells may have distinct roles in regulating humoral immunity to hCMV. Overall, the results of the study provide valuable insights into the coordination of NK cell marker expression and IgG response in hCMV infection.

1. Erokhina S.A., Streltsova M.A., Kanevskiy L.M., Grechikhina M.V., Sapozhnikov A.M., Kovalenko E.I. HLA-DR-Expressing NK cells: effective killers suspected for antigen presentation. J. Leukoc. Biol. 2021, Vol. 109, pp. 327-337.

2. Gumá M., Budt M., Sáez A., Brckalo T., Hengel H., Angulo A., López-Botet M. Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblasts. Blood, 2006, Vol. 107, no. 9, pp. 3624-3631.

3. Kenneson A., Cannon M.J. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev. Med. Virol., 2007, Vol.17, no. 4, pp. 253-276.

4. Kobyzeva P.A., Streltsova M.A., Erokhina S.A., Kanevskiy L.M., Telford W.G., Sapozhnikov A.M., Kovalenko E.I. CD56dim CD57- NKG2C+ NK cells retaining proliferative potential are possible precursors of CD57+ NKG2C+ memory-like NK cells. J. Leukoc. Biol., 2020, Vol. 108, no. 4, pp. 1379-1395.

5. Kovalenko E.I., Streltsova M.A., Kanevskiy L.M., Erokhina S.A., Telford W.G. Identification of Human Memory-Like NK Cells. Curr. Protoc. Cytom., 2017, Vol. 79, 9.50.1-9.50.11. doi: 10.1002/cpcy.13.

6. Lopez-Botet M., Muntasell A., Martinez-Rodriguez J.E., Lopez-Montanes M., Costa-Garcia M., Pupuleku A. Development of the adaptive nk cell response to human cytomegalovirus in the context of aging. Mech. Ageing Dev., 2016, Vol. 158, pp. 23-26.

7. Pende D., Falco M., Vitale M., Cantoni C., Vitale C., Munari E., Bertaina A., Moretta F., Del Zotto G., Pietra G., Mingari M.C., Locatelli F., Moretta L. Killer Ig-like receptors (KIRs): Their role in NK cell modulation and developments leading to their clinical exploitation. Front. Immunol., 2019, Vol. 10, 1179. doi: 10.3389/fimmu.2019.01179.

8. Wu Z., Sinzger C., Frascaroli G., Reichel J., Bayer C., Wang L., Schirmbeck R., Mertens T. Human cytomegalovirus-induced nkg2c(hi) cd57(hi) natural killer cells are effectors dependent on humoral antiviral immunity. J. Virol., 2013, Vol. 87, pp. 7717-7725.

9. Yokoyama W.M., Kim S., French A.R. The dynamic life of natural killer cells. Annu. Rev. Immunol., 2004, Vol. 22, pp. 405-429.

10. Zdziarski P. CMV-specific immune response-new patients, new insight: central role of specific IgG during infancy and long-lasting immune deficiency after allogenic stem cell transplantation. Int. J. Mol. Sci., 2019, Vol. 20, no. 2, 271. doi: 10.3390/ijms20020271.