Depletion of MHC class II invariant chain peptide or γ–δ T-cells ameliorates experimental preeclampsia

Abstract

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.

Mechanisms of Key Innate Immune Cells in Early- and Late-Onset Preeclampsia

“…The role of γδ T cells has not yet been determined in preeclampsia, but increases in the production of pro-inflammatory stimuli, interferon (IFN)-γ & IL-17, by γδ T cells have been reported in women with idiopathic recurrent pregnancy loss ( 143 ). Furthermore, in mice, a competitive antagonist binding of the histocompatibility complex (MHC) class II found on the surface of ɤδ T cells, resulted in the reduction of their immunological capabilities ( 144 ). The ɤδ T cell “knockout mice” displayed a resistance to developing preeclampsia-like features, implying that these cells could have a role in the pathogenesis of the condition ( 144 ).…”

“…Furthermore, in mice, a competitive antagonist binding of the histocompatibility complex (MHC) class II found on the surface of ɤδ T cells, resulted in the reduction of their immunological capabilities ( 144 ). The ɤδ T cell “knockout mice” displayed a resistance to developing preeclampsia-like features, implying that these cells could have a role in the pathogenesis of the condition ( 144 ). In the same study, preeclamptic placentae demonstrated significantly increased levels of γδ T cells ( 144 ).…”

“…The ɤδ T cell “knockout mice” displayed a resistance to developing preeclampsia-like features, implying that these cells could have a role in the pathogenesis of the condition ( 144 ). In the same study, preeclamptic placentae demonstrated significantly increased levels of γδ T cells ( 144 ).…”

Antagonism of major histocompatibility complex class II invariant chain peptide during chronic lipopolysaccharide treatment rescues autoregulatory behavior

“…MHC-II processing and presentation is critical for bridging acute responses involving the innate immune system, with the long-term adaptive immune response. Over the years, research has formed the basis for mechanistic and functional links between TLRs and MHC-II molecules (13,20,29,41,46) Intervention with CAP, a major histocompatibility complex class II-associated invariant chain peptide antagonist, rescued renal autoregulatory behavior during 14-day LPS administration. A: effect of perfusion pressure changes on afferent arteriolar diameter in kidneys from saline (0.9% NaCl sq)-, LPS (0.1 mg•kg Ϫ1 •day Ϫ1 sq)-, and LPS ϩ CAP (3 mg/kg ip daily)-treated male rats.…”

CLDN3 expression and function in pregnancy‑induced hypertension

“…Risk factors of the disease include obesity, pre-pregnancy hypertension, diabetes and old age ( 7 ). The causes for pregnancy-induced hypertension remain to be elucidated; however, they may be associated with changes in the immune system such as histocompatibility antigen-associated immunological abnormalities ( 8 ). In addition, genetic susceptibility may also be involved in the pathogenesis of this disease ( 9 , 10 ).…”