CD91 Derived Treg Epitope Modulates Regulatory T Lymphocyte Response, Regulates Expression of Costimulatory Molecules on Antigen-Presenting Cells, and Rescues Pregnancy in Mouse Pregnancy Loss Model.

Anna Ewa Kedzierska,Anna Slawek,Anna Chelmonska-Soyta,Tomasz Grabowski,Daria Lorek

doi:10.3390/ijms22147296

Abstract

The loss of immune tolerance to fetal antigens may result in reproductive failure. The downregulated number and activity of T regulatory lymphocytes, which are critical for the establishment of immune tolerance to fetal antigens, during pregnancy may lead to miscarriage. The adoptive transfer of Tregs prevents fetal loss in abortion-prone mice. Recently, we demonstrated that the administration of tregitopes, which are short peptides found in human and mouse immunoglobulins (IgGs), decreased the incidence of abortions in female CBA/J mice mated with DBA/2J mice. Here, two non-IgG source peptides (SGS and LKD) that can potentially bind to the major histocompatibility complex II (MHC II) with high affinity and induce Treg expansion were designed in silico. The immune dysregulation-induced pregnancy failure mouse model was used to evaluate the effect of SGS and LKD on immune response and pregnancy outcome. The fetal death rate in the SGS-treated group was lower than that in the phosphate-buffered saline-treated group. SGS and LKD upregulated the splenic pool of Tregs and modulated the T-helper cell (Th1)/Th2-related cytokine response at the preimplantation stage. Additionally, SGS and LKD downregulated the expression of CD80 and MHC class II molecules in splenic CD11c+ antigen-presenting cells. Thus, SGS treatment can result in beneficial pregnancy outcomes. Additionally, SGS peptide-mediated immunomodulation can be a potential therapeutic strategy for immune dysregulation-induced pregnancy failure.

Highlights

The cross-talk between the mother and the conceptus is one of the fundamental prerequisites for the development of a healthy pregnancy
The findings of this study suggested that the early administration of CD91 derived Treg epitope (SGS peptide) induces the expansion of Tregs and may prevent abortions in an abortion-prone mouse model
Based on a previously reported in silico model [24], two potential non-IgG source Treg epitopes that can induce the expansion of Tregs were identified in this study

Summary

Introduction

The cross-talk between the mother and the conceptus is one of the fundamental prerequisites for the development of a healthy pregnancy. It is well known that regulatory T lymphocytes (Tregs) and regulatory B lymphocytes (Bregs) contribute to the development of tolerance to fetal antigens [2,3] In both humans and mice, the proportion of Tregs in pregnant individuals is higher than that of those in non-pregnant controls. We demonstrated that the early administration of T regulatory cell epitopes (tregitopes), which are short peptides found in the light and heavy chains of human and mouse immunoglobulins (IgGs), decreased the incidence of abortion in abortion-prone mice [16]. These tregitopes may bind to the major histocompatibility complex (MHC II)-binding groove, and this complex is presented to Tregs, which results in the activation and proliferation of Tregs. The identified SGS peptide meets the criteria of a tregitope, as its sequence is present in prevalent human proteins, conservative across many species, and can bind to the human leukocyte antigen-DR isotype (HLA-DR) [23]

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