NLRP2 is a suppressor of NF-ƙB signaling and HLA-C expression in human trophoblasts†,‡.
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.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Tamara
T
Tilburgs
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Torsten B
TB
Meissner
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.|Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.
Leonardo M R
LMR
Ferreira
Department of Immunohematology and Blood transfusion, Leiden University Medical Center, Leiden, Netherlands.
Arend
A
Mulder
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Kiran
K
Musunuru
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.|Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York, USA.
Junqiang
J
Ye
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Jack L
JL
Strominger
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D005805:Genes, MHC Class I / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014327:Trophoblasts / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D015236:HLA-C Antigens; D016328:NF-kappa B; C495732:NLRP2 protein, human; D012333:RNA, Messenger
HLA-G; MHC; NOD-like receptor; inflammasome; pregnancy