Progesterone Dampens Immune Responses in In Vitro Activated CD4+ T Cells and Affects Genes Associated With Autoimmune Diseases That Improve During Pregnancy

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.

Progesterone Inhibits the Establishment of Activation-Associated Chromatin During TH1 Differentiation

“…Indeed, these changes were highly enriched in pathways involved in T-cell activation, the first crucial step involved in T-cell lineage commitment, both in peaks associated to promoter and distal elements. The dampening effect of P4 on T-cell activation are in line with previous findings ( 10 , 11 , 44 ), although here we provide a more fine-grained time series analysis of how P4 affects T-cell activation, in particularly related to T H 1 differentiation. More in-depth analysis revealed that the major TFs regulating these changes were dominated by well-known TFs involved in T-cell activation such as BATF , FOS, FOSL1, FOSL2, JUN and JUNB.…”

“…To this end, naïve T H cells cultured under T H 1 polarizing conditions alone were compared to T H cells polarized in the presence of P4 ( Figure 1 ). As we have previously shown that P4 induces large transcriptomic changes during T cell activation ( 10 ), we wanted to gain further functional insights into underlying gene regulatory machinery. We therefore used correlation between ATAC-and RNA-seq to identify more robust changes induced by P4 that are transmitted across both omics.…”

“…In fact, P4 treatment before onset and during ongoing disease reduces clinical severity and shows neuroprotective effects in the MS animal model experimental autoimmune encephalomyelitis (EAE) (47)(48)(49)(50). We have previously shown that P4 affects disease-associated genes related to several immune-mediated diseases (10), including MS and RA. In agreement with these findings, we found that the downregulatory changes induced by P4 during T H 1 differentiation were also significantly enriched for diseases such as MS and RA.…”

“…Indeed, exposure of T cells to P4 has previously been shown to modulate T H 1 responses, mainly through dampening of T H 1associated cytokine secretion (6)(7)(8)(9). Furthermore, P4 has been shown to limit T cell activation and proliferation (10,11), possibly impeding the action of autoreactive T H 1 cells. A deeper understanding of how P4 influences T H 1 activation and differentiation could provide further insights into its role in disease modulation during pregnancy and potential as a novel therapy in T H 1-related autoimmune diseases.…”

Cytokines, Hormones and Cellular Regulatory Mechanisms Favoring Successful Reproduction

“…We can consider the use of the pregnancy-related hormone progesterone, which was shown as early as in 1983, to have anti-inflammatory and immunosuppressive properties (55) because of which it was referred to as "Nature's immunosuppressant" (56). Progesterone suppresses several cellmediated immune activities including the activation and proliferation of lymphocytes (57) and reverses many of the events that occur during T cell activation (58).…”