Progesterone Modulation of Pregnancy-Related Immune Responses.

Nishel M Shah,Mark R Johnson,Nesrina Imami

doi:10.3389/fimmu.2018.01293

Nishel M Shah, Mark R Johnson + Show 1 more

Open Access

https://doi.org/10.3389/fimmu.2018.01293

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Abstract

Progesterone (P4) is an important steroid hormone for the establishment and maintenance of pregnancy and its functional withdrawal in reproductive tissue is linked with the onset of parturition. However, the effects of P4 on adaptive immune responses are poorly understood. In this study, we took a novel approach by comparing the effects of P4 supplementation longitudinally, with treatment using a P4 antagonist mifepristone (RU486) in mid-trimester pregnancies. Thus, we were able to demonstrate the immune-modulatory functions of P4. We show that, in pregnancy, the immune system is increasingly activated (CD38, CCR6) with greater antigen-specific cytotoxic T cell responses (granzyme B). Simultaneously, pregnancy promotes a tolerant immune environment (IL-10 and regulatory-T cells) that gradually reverses prior to the onset of labor. P4 suppresses and RU486 enhances antigen-specific CD4 and CD8 T cell inflammatory cytokine (IFN-γ) and cytotoxic molecule release (granzyme B). P4 and RU486 effectively modulate immune cell-mediated interactions, by regulating differentiated memory T cell subset sensitivity to antigen stimulation. Our results indicate that P4 and RU486, as immune modulators, share a reciprocal relationship. These data unveil key contributions of P4 to the modulation of the maternal immune system and suggests targets for future modulation of maternal immune function during pregnancy.

Highlights

Progesterone (P4) plays a key role in the establishment and maintenance of pregnancy and its withdrawal causes the onset of labor [1, 2]
Before investigating the effects of P4, leukocyte functional and phenotypic profiles were analyzed longitudinally in un-supplemented pregnancies. This established the effects of pregnancy and advancing gestation as well as providing a control group
Our results showed that labor and delivery was characterized by a peak in responses to measles and CMV (Figures 1B,C) whole lysates, as well as tetanus toxoid (TTOX) (Figure S1 in Supplementary Material), purified protein derivative (PPD) antigens, and FEC peptide pool (Figure 1A)

Summary

Introduction

Progesterone (P4) plays a key role in the establishment and maintenance of pregnancy and its withdrawal causes the onset of labor [1, 2]. Human PBMCs are thought to express a number of endocrine receptors including: mPR, GR, and estrogen receptors [4, 6, 7, 10]. GR engagement increases regulatory T cell (Treg) immunesuppressive function, and P4 binding to GR is thought to be responsible for this finding in pregnancy [8, 9]. In contrast to most animal models of pregnancy, where there is a systemic withdrawal of P4 prior to the onset of labor, in the human, the literature suggests that there is a functional withdrawal at the level of the PR at the end of pregnancy [11].

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