Natural killers in pregnancy: servants of two masters

Krechetov, S. P.; Khoroshkeeva, O. V.; Jankevic, T. E.; Borovikov, P. I.; Shirokov, Y. V.; Krechetova, L. V.; Tetruashvili, N. K.; Trofimov, D. Y.; Sukhikh, G. T.

doi:10.1101/2025.11.11.685990

bioRxiv · 10.1101/2025.11.11.685990

Natural killers in pregnancy: servants of two masters

Krechetov, S. P.·Khoroshkeeva, O. V.·Jankevic, T. E.·Borovikov, P. I.·Shirokov, Y. V.·Krechetova, L. V.·Tetruashvili, N. K.·Trofimov, D. Y.·Sukhikh, G. T.

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Abstract

The absence of maternal immune rejection of a haploidentical fetus remains unexplained. We hypothesize that the presence of different HLA antigens on trophoblasts and maternal cells via killer cell immunoglobulin-like receptors (KIRs) provides two-way tuning (education) of decidual natural killer cells (dNK) with the appearance of allo- (HvG) and autoreactive (HvH) dNK. Disturbances in dNKHvG and dNKHvH representation may lead to abnormalities in placental development and pregnancy pathology. Our data show that recurrent pregnancy loss is not associated with specific HLA and KIR genotypes in mother and fetus, although the peculiarities of tuning involving KIR3DL2 may affect pregnancy outcome. Mathematical modeling shows the dependence of dNKHvG and dNKHvH representation on the probability of random KIR gene expression. The new description of NK cell involvement in the immune response in the placenta via two-way tuning is applicable to all cases where there are target cells with normal and different "guest" HLA expression (viral infections, tumors, etc.) Graphic abstract (Cover work) O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/685990v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1e122a1org.highwire.dtl.DTLVardef@1a898caorg.highwire.dtl.DTLVardef@1c721b5org.highwire.dtl.DTLVardef@760a94_HPS_FORMAT_FIGEXP M_FIG C_FIG Image of fetus in utero in graphic abstract adapted from Servier Medical Art (https://smart.servier.com), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/) HighlightsA hypothesis has been proposed according to which random expression of NK cell receptor genes in combination with two-way tuning (education) of NK cells by different affinity pairs of inhibitory killer cell immunoglobulin-like receptors (KIRs) and their ligands on decidual cells and trophoblasts leads to the presence of populations of maternal decidual NK cells with allo- and autoreactivity in the placenta. It has been shown that the features of the HLA and KIR genotypes of the mother and fetus are not the underlying cause of habitual miscarriage, although genetic features can affect the course of pregnancy. Model calculations of the representation of auto- and alloreactive maternal decidual NK cells show that the effectiveness of their participation in the structural and functional reorganization of the placenta should depend on the probability of KIR gene expression. The hypothesis of two-way tuning of NK cells in the presence of different target cells with normal and different "guest" HLA expressions is applicable to describe the involvement of the innate immune system in the response to pregnancy, viral infection, inflammation, wounds, tumors, and transplantation.

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Krechetov, S. P., Khoroshkeeva, O. V., Jankevic, T. E., Borovikov, P. I., Shirokov, Y. V., Krechetova, L. V., Tetruashvili, N. K., Trofimov, D. Y., Sukhikh, G. T.. 2025-11-12. Natural killers in pregnancy: servants of two masters. https://doi.org/10.1101/2025.11.11.685990

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