Excessive innate immune system activation and inflammation during pregnancy can lead to organ injury and dysfunction and preeclampsia (PE); however, the molecular mechanisms involved are unknown. We tested the hypothesis that Toll-like receptor (TLR) activation induces major histocompatibility complex (MHC) class II invariant chain peptide (CLIP) expression on immune cells, makes them pro-inflammatory, and are necessary to cause PE-like features in mice. Treatment with VG1177, a competitive antagonist peptide for CLIP in the groove of MHC class II, was able to both prevent and treat PE-like features in mice. We then determined that γ–δ T cells are critical for the development of PE-like features in mice since γ–δ T-cell knockout mice, like CLIP deficient mice, are resistant to developing PE-like features. Placentas from women with PE exhibit significantly increased levels of γ–δ T cells. These preclinical data demonstrate that CLIP expression and activated γ–δ T cells are responsible for the development of immunologic PE-like features and that temporarily antagonizing CLIP and/or γ–δ T cells may be a therapeutic strategy for PE.

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