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7 March 2017 NLRP2 is a suppressor of NF-B signaling and HLA-C expression in human trophoblasts
Tamara Tilburgs, Torsten B. Meissner, Leonardo M. R. Ferreira, Arend Mulder, Kiran Musunuru, Junqiang Ye, Jack L. Strominger
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Abstract

During pregnancy, fetal extravillous trophoblasts (EVT) play a key role in the regulation of maternal T cell and NK cell responses. EVT display a unique combination of human leukocyte antigens (HLA); EVT do not express HLA-A and HLA-B, but do express HLA-C, HLA-E, and HLA-G. The mechanisms establishing this unique HLA expression pattern have not been fully elucidated. The major histocompatibility complex (MHC) class I and class II transcriptional activators NLRC5 and CIITA are expressed neither by EVT nor by the EVT model cell line JEG3, which has an MHC expression pattern identical to that of EVT. Therefore, other MHC regulators must be present to control HLA-C, HLA-E, and HLA-G expression in these cells. CIITA and NLRC5 are both members of the nucleotide-binding domain, leucine-rich repeat (NLR) family of proteins. Another member of this family, NLRP2, is highly expressed by EVT and JEG3, but not in maternal decidual stromal cells. In this study, transcription activator-like effector nuclease technology was used to delete NLRP2 in JEG3. Furthermore, lentiviral delivery of shRNA was used to knockdown NLRP2 in JEG3 and primary EVT. Upon NLRP2 deletion, Tumor Necrosis Factor-α (TNFα)-induced phosphorylation of NF-KB p65 increased in JEG3 and EVT, and more surprisingly a significant increase in constitutive HLA-C expression was observed in JEG3. These data suggest a broader role for NLR family members in the regulation of MHC expression during inflammation, thus forming a bridge between innate and adaptive immune responses. As suppressor of proinflammatory responses, NLRP2 may contribute to preventing unwanted antifetal responses.

Summary Sentence

By modulating the NF-KB pathway and HLA-C expression on human trophoblasts, NLRP2, may contribute to preventing detrimental inflammatory responses at the maternal-fetal interface.

© The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please journals.permissions@oup.com
Tamara Tilburgs, Torsten B. Meissner, Leonardo M. R. Ferreira, Arend Mulder, Kiran Musunuru, Junqiang Ye, and Jack L. Strominger "NLRP2 is a suppressor of NF-B signaling and HLA-C expression in human trophoblasts," Biology of Reproduction 96(4), 831-842, (7 March 2017). https://doi.org/10.1093/biolre/iox009
Received: 12 December 2016; Accepted: 28 February 2017; Published: 7 March 2017
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