Abstract
The changes in progesterone (P4) levels during and after pregnancy coincide with the temporary improvement and worsening of several autoimmune diseases like multiple sclerosis (MS) and rheumatoid arthritis (RA). Most likely immune-endocrine interactions play a major role in these pregnancy-induced effects. In this study, we used next generation sequencing to investigate the direct effects of P4 on CD4+ T cell activation, key event in pregnancy and disease. We report profound dampening effects of P4 on T cell activation, altering the gene and protein expression profile and reversing many of the changes induced during the activation. The transcriptomic changes induced by P4 were significantly enriched for genes associated with diseases known to be modulated during pregnancy such as MS, RA and psoriasis. STAT1 and STAT3 were significantly downregulated by P4 and their downstream targets were significantly enriched among the disease-associated genes. Several of these genes included well-known and disease-relevant cytokines, such as IL-12β, CXCL10 and OSM, which were further validated also at the protein level using proximity extension assay. Our results extend the previous knowledge of P4 as an immune regulatory hormone and support its importance during pregnancy for regulating potentially detrimental immune responses towards the semi-allogenic fetus. Further, our results also point toward a potential role for P4 in the pregnancy-induced disease immunomodulation and highlight the need for further studies evaluating P4 as a future treatment option.
Highlights
Pregnancy represents a unique immunological condition as the maternal immune system is able to tolerate the presence of the semi-allogenic fetus
In order to examine the effect of P4 on CD4+ T cells and T cell activation, we established an in vitro model where primary human CD4+ T cells were pre-incubated with P4 prior to activation, reflecting the in vivo situation where the T cells would constantly be exposed to P4 prior to antigen challenge
Activation of CD4+ T cells in the presence of different concentrations of P4 decreased the level of activation of the cells in a dose-dependent manner, with reduced proportion of both CD69 and CD25 expressing cells, where exposure to the highest concentration of P4 (50 μM) resulted in the largest overall decrease (6 hrs: CD69 p
Summary
Pregnancy represents a unique immunological condition as the maternal immune system is able to tolerate the presence of the semi-allogenic fetus. This immunological tolerance is thought to arise from extensive immune and endocrine alterations induced during pregnancy [1, 2] orchestrated by the increased levels of the steroid hormones such as progesterone (P4), which is essential for the establishment and maintenance of pregnancy [3,4,5]. An important immune-modulatory role of P4 in vivo is indicated by the pregnancy-related improvement and subsequent worsening of autoimmune diseases, such as multiple sclerosis (MS) and rheumatoid arthritis (RA), which coincide with the time points during and after pregnancy when P4 levels are the highest and lowest, respectively [12,13,14]. A role for P4 as a potent immunosuppressor is supported by in vivo studies showing involvement of P4 in response to allogenic and xenogenic transplantation [25,26,27] and in graft rejection in humans [28]
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