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Expression of KIR2DS1 by Decidual Natural Killer Cells Increases Their Ability to Control Placental HCMV Infection

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Expression of KIR2DS1 by Decidual Natural Killer Cells Increases Their Ability to Control Placental HCMV Infection Expression of KIR2DS1 by decidual natural killer cells increases their ability to control placental HCMV infection Ângela C. Crespoa,b, Jack L. Stromingera,1, and Tamara Tilburgsa,1 aDepartment of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138; and bPhD Program in Experimental Biology and Biomedicine, Center for Neurosciences and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal Contributed by Jack L. Strominger, November 8, 2016 (sent for review August 22, 2016; reviewed by Marcus Altfeld and Wayne M. Yokoyama) The combination of the activating killer cell Ig-like receptor 2DS1 with the ability to secrete beneficial cytokines and growth factors, (KIR2DS1) expressed by maternal decidual natural killer cells (dNK) and especially granulocyte–monocyte colony stimulation factor (GM- the presence of its ligand, the HLA-C allotype HLA-C2, expressed by CSF), to facilitate trophoblast invasion and placental growth (2). fetal trophoblasts, reduces the risk of developing pregnancy complica- This increase in cytokine production was observed when dNK tions. However, no molecular or cellular mechanism explains this were stimulated with anti-KIR2DS1 antibodies and classical NK genetic correlation. Here we demonstrate that KIR2DS1+ dNK acquired target cells that expressed HLA-C2. However, primary EVT do higher cytotoxic function than KIR2DS1− dNK when exposed to hu- not elicit cytokine responses by dNK even when KIR2DS1 and man cytomegalovirus (HCMV)-infected decidual stromal cells (DSC), HLA-C2 are present (8). Therefore, these genetic associations particularly when DSCs express HLA-C2. Furthermore, dNK were un- demand further investigation into the molecular and cellular able to degranulate or secrete cytokines in response to HCMV-infected mechanisms underlying the reduced pregnancy risk linked to primary fetal extravillous trophoblasts. This emphasizes the immuno- activating KIR, and in particular KIR2DS1. Our laboratory and logical challenge to clear placental viral infections within the im- others have shown that dNK have many differences in gene ex- mune-privileged placenta. Activation of dNK through KIR2DS1/ pression, cytokine secretion, and cytolytic capacity in comparison – HLA-C2 interaction increases their ability to respond to placental with pNK (2, 9 12). Furthermore, dNK form immune synapses HCMV infection and may limit subsequent virus-induced placental with EVT in which perforin is not localized to the synaptic re- pathology. This mechanism is directly related to how KIR2DS1 gion, a feature typical of a nonlytic synapse (13). During these expressed by dNK reduces development of severe pregnancy compli- immune synapses, dNK acquired HLA-G from the EVT through + cations such as miscarriages and preterm delivery. trogocytosis. Interestingly, KIR2DS1 dNK incorporated in- creased levels of HLA-G into their membrane, suggesting that human | HLA-C | trophoblast | pregnancy | immune tolerance prolonged intracellular signaling and possibly distinct functional properties may result. In addition to the beneficial effect of KIR2DS1 in pregnancy, ne of the most interesting observations in the past decade in individuals who carry the KIR-B haplotype have a significantly Oreproductive immunology research is that women who have improved outcome after viral infections (14, 15). The combined the activating killer cell Ig-like receptor 2DS1 (KIR2DS1)in presence of KIR3DS1 and its ligand HLA-Bw4 was associated their genome have lower risks of developing pregnancy compli- with slower progression to AIDS, lower viral load, and slower cations. In contrast, women who lack KIR2DS1 are at increased decline of CD4+ T cells (14, 16). KIR3DS1 and KIR2DS1 were risk (1, 2). The protective effect of maternal KIR2DS1 expres- sion is most obvious when the fetus expresses the ligand for Significance KIR2DS1, the HLA-C2 group allotype of HLA-C (2). Recently, the presence of KIR2DS5 was also associated with lower risk of The etiology of pregnancy complications such as miscarriage, developing pregnancy complications in African women, whereas preterm birth, and preeclampsia are largely unknown. The the effect of KIR2DS1 seems to be characteristic of European combination of the maternal Killer Immunoglobulin-like Re- populations (3). The presence or absence of the KIR2DS1 gene is ceptor-2DS1 (KIR2DS1) with fetal HLA-C was identified as a due to the various rearrangements in the KIR locus during evo- factor determining risk of pregnancy complications. Thus de- lution (4, 5). This resulted in two main KIR haplotypes, KIR-A cidual natural killer cells (dNK) that express high levels of KIR and KIR-B. The KIR-A haplotype lacks most activating KIR may have a predominant role in pregnancy outcome. Although including KIR2DS1, whereas the KIR-B haplotypes include one the dNK effect has been associated with cytokine and growth or more activating KIR genes. Both the KIR-A and KIR-B factor production to promote placentation, here we show that haplotypes contain multiple inhibitory KIR including KIR2DL1 the combination of maternal KIR and HLA-C is also a factor that that, similarly to KIR2DS1, binds HLA-C2 molecules. Although determines protection against placental human cytomegalovirus engagement of KIR2DL1 with HLA-C2 leads to inhibition of (HCMV) infections. Expression of KIR2DS1 by dNK increases the natural killer (NK) function (e.g., cytotoxicity), engagement of cytotoxic response of dNK to HLA-C2+ HCMV-infected maternal KIR2DS1 with HLA-C2 leads to NK activation (6). Protection decidual stromal cells, preventing viral spread and placental from pregnancy complications by the KIR-B haplotype includes pathology. severe maternal and fetal syndromes that occur in high fre- quencies in the population such as miscarriages (20–30%), fetal Author contributions: Â.C.C., J.L.S., and T.T. designed research; Â.C.C. and T.T. performed growth restriction (3–10%), and preeclampsia (3–5%) (1, 2). research; Â.C.C. and T.T. analyzed data; and Â.C.C., J.L.S., and T.T. wrote the paper. KIR2DS1 is expressed with increased frequency on decidual Reviewers: M.A., Heinrich-Pette-Institut; and W.M.Y., Washington University School NK cells (dNK) at the maternal–fetal interface compared with of Medicine. peripheral blood NK cells (pNK) (7). The current hypothesis The authors declare no conflict of interest. suggests that the protective effect of KIR2DS1 lies in the acti- 1To whom correspondence may be addressed. Email: [email protected] or vation of dNK through the binding of HLA-C2 molecules [email protected]. expressed by fetal extravillous trophoblasts (EVT). The activa- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. tion through HLA-C2/KIR2DS1 is postulated to provide dNK 1073/pnas.1617927114/-/DCSupplemental. 15072–15077 | PNAS | December 27, 2016 | vol. 113 | no. 52 www.pnas.org/cgi/doi/10.1073/pnas.1617927114 Downloaded by guest on October 1, 2021 shown to be protective against respiratory papillomatosis caused KIR2DL1 positive (L1+)andKIR2DL1negative(L1−)(Fig. by human papillomavirus (17). Moreover, KIR3DS1+ NK cells 1A). Among the KIR2DS1 gene carriers, the frequency of both inhibited HIV-1 replication in vitro (18). Finally, activating KIR L1−S1+ and L1+S1+ was significantly higher in dNK than in play a role in NK-mediated clearance of human cytomegalovirus pNK (Fig. 1B). In KIR2DS1− individuals, L1+ NK were more (HCMV) infection following stem-cell or solid-organ trans- frequent in decidua than in blood (Fig. 1B). These results confirm plantation (19–21). The importance of activating receptors for previous reports demonstrating a skewing of dNK receptor ex- self-MHC in the clearance of HCMV infection has also been pression toward recognition of HLA-C (for which KIR2DL1 and demonstrated in mice, where NK cells expressing activating re- KIR2DS1 are receptors) and, particularly, the potential of dNK ceptors displayed increased responses to infected cells and were to develop an activating response to HLA-C2 through KIR2DS1 involved in the differentiation of murine cytomegalovirus (2, 35). (MCMV)-specific memory NK cells (22). The NK receptors, their HLA ligands, and clinical benefits are listed in SI Appendix, KIR2DS1 Expression on dNK Correlated with a Relatively High Content Table S1. Viral infections such as HCMV, HIV, herpes simplex of Cytolytic Proteins. To determine whether the presence of virus, and influenza virus can cause severe maternal and fetal KIR2DS1 influenced the cytolytic potential of NK cells, freshly iso- morbidity when they occur during pregnancy (23–25). Infections lated dNK and pNK were examined for the expression of the cyto- have been reported to cause spontaneous abortions at a rate of lytic molecules granzyme B, perforin, and the 9-kDa active form of about 4%. However, difficulties in demonstrating the pathogenic granulysin (36, 37). A higher percentage of dNK expressed granulysin role of a wide variety of pathogens may result in under-diagnosis compared with pNK, and granulysin was also expressed at a higher (26). HCMV is the most common congenital infection and oc- level in dNK (SI Appendix,Fig.S1A–C). pNK expressed higher levels curs in 0.5–2% of all live births. HCMV infects the placenta of perforin compared with dNK, whereas no difference was found before the fetus and can inhibit trophoblast differentiation and between expression of granzyme B by dNK and pNK. Furthermore, invasion, which can lead to placental insufficiency and fetal dNK and pNK of KIR2DS1+ individuals were divided into the four growth restriction (27–30). In addition to NK cells, CD8+ T cells NK subtypes, and S1+ (both L1−S1+ and L1+S1+) dNK expressed are the most important cells to respond and clear viral infections higher levels of granzyme B, perforin, and granulysin compared with (31). However, in early pregnancy decidual tissue, CD8+ T cells the L1−S1− dNK subset (Fig. 1 C and D). The increased expression form a minor population representing only 2–7% of total lym- of cytolytic molecules was specific for S1+ dNK and was not observed phocytes. Furthermore, decidual CD8+ effector-memory T cells in S1+ pNK (Fig.
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