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Expression of KIR2DS1 by decidual natural killer cells increases their ability to control placental HCMV infection.

ABSTRACT: The combination of the activating killer cell Ig-like receptor 2DS1 (KIR2DS1) expressed by maternal decidual natural killer cells (dNK) and the presence of its ligand, the HLA-C allotype HLA-C2, expressed by fetal trophoblasts, reduces the risk of developing pregnancy complications. However, no molecular or cellular mechanism explains this genetic correlation. Here we demonstrate that KIR2DS1+ dNK acquired higher cytotoxic function than KIR2DS1- dNK when exposed to human cytomegalovirus (HCMV)-infected decidual stromal cells (DSC), particularly when DSCs express HLA-C2. Furthermore, dNK were unable to degranulate or secrete cytokines in response to HCMV-infected primary fetal extravillous trophoblasts. This emphasizes the immunological challenge to clear placental viral infections within the immune-privileged placenta. Activation of dNK through KIR2DS1/HLA-C2 interaction increases their ability to respond to placental HCMV infection and may limit subsequent virus-induced placental pathology. This mechanism is directly related to how KIR2DS1 expressed by dNK reduces development of severe pregnancy complications such as miscarriages and preterm delivery.

SUBMITTER: Crespo AC

PROVIDER: S-EPMC5206558 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Expression of KIR2DS1 by decidual natural killer cells increases their ability to control placental HCMV infection.

Crespo Ângela C ÂC Strominger Jack L JL Tilburgs Tamara T

Proceedings of the National Academy of Sciences of the United States of America 20161212 52

The combination of the activating killer cell Ig-like receptor 2DS1 (KIR2DS1) expressed by maternal decidual natural killer cells (dNK) and the presence of its ligand, the HLA-C allotype HLA-C2, expressed by fetal trophoblasts, reduces the risk of developing pregnancy complications. However, no molecular or cellular mechanism explains this genetic correlation. Here we demonstrate that KIR2DS1+ dNK acquired higher cytotoxic function than KIR2DS1- dNK when exposed to human cytomegalovirus (HCMV)-i ...[more]

PMID: 27956621

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Project description:Natural Killer (NK) cells have been found to be anergic, exhausted and pro-angiogenic in cancers. NK cell from healthy donors, exposed to TGFβ, acquire the CD56brightCD9+CD49a+ decidual-like-phenotype, together with decreased levels of NKG2D activation marker, increased levels of TIM-3 exhaustion marker, similar to cancer-associated NK cells. Tissue inhibitors of metalloproteases (TIMPs) exert dual roles in cancer. The role of TIMPs in modulating immune cells is a very novel concept, and the present is the first report studying their ability to contrast TGFβ action on NK cells. Here, we investigated the effects of TIMP1 and TIMP2 recombinant proteins in hindering decidual-like markers in NK cells, generated by polarizing cytolytic NK cells with TGFβ. The effects of TIMP1 or TIMP2 on NK cell surface antigens were determined by multicolor flow cytometry. We found that TIMP1 and TIMP2 were effective in interfering with TGFβ induced NK cell polarization towards a decidual-like-phenotype. TIMP1 and TIMP2 counteracted the effect of TGFβ in increasing the percentage of CD56bright, CD16-, CD9+ and CD49a+, and restoring normal levels for TIMP 1 and 2 also inhibited decrease levels of the activation marker NKG2D induced by TGFβ and decreased the TGFβ upregulated exhaustion marker TIM-3. NK cell degranulation capabilities against K562 cells were also decreased by TGFβ and not by TIMP1 or TIMP2. TIMP1 treatment could partially restore degranulation marker CD107a expression. Treatment with recombinant TIMP-1 or TIMP-2 showed a trend, although not statistically significant, to decrease CD49a+ and TIM-3+ expression and increase NKG2D in peripheral blood NK cells exposed to conditioned media from colon cancer cell lines. Our results suggest a potential role of TIMPs in controlling the tumor-associated cytokine TGFβ-induced NK cell polarization. Given the heterogeneity of released factors within the TME, it is clear that TGFβ stimulation represents a model to prove TIMP's new properties, but it cannot be envisaged as a soloist NK cell polarizing agent. Therefore, further studies from the scientific community will help defining TIMPs immunomodulatory activities of NK cells in cancer, and their possible future diagnostic-therapeutic roles.

Dataset Information

Expression of KIR2DS1 by decidual natural killer cells increases their ability to control placental HCMV infection.

Publications

Expression of KIR2DS1 by decidual natural killer cells increases their ability to control placental HCMV infection.

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