Pregnancy is one of the strongest inducers of immunological tolerance. Disease activity of many autoimmune diseases including multiple sclerosis (MS) is temporarily suppressed by pregnancy, but little is known about the underlying molecular mechanisms. Here, we investigated the endocrine regulation of conventional and regulatory T cells (Tregs) during reproduction. In vitro, we found the pregnancy hormone progesterone to robustly increase Treg frequencies via promiscuous binding to the glucocorticoid receptor (GR) in T cells. In vivo, T-cell-specific GR deletion in pregnant animals undergoing experimental autoimmune encephalomyelitis (EAE), the animal model of MS, resulted in a reduced Treg increase and a selective loss of pregnancy-induced protection, whereas reproductive success was unaffected. Our data imply that steroid hormones can shift the immunological balance in favor of Tregs via differential engagement of the GR in T cells. This newly defined mechanism confers protection from autoimmunity during pregnancy and represents a potential target for future therapy.multiple sclerosis | autoimmunity | pregnancy | Treg | steroid hormones R eproduction is fundamental to the maintenance and evolution of species. To ensure successful pregnancy, mothers have to establish robust immunological tolerance toward the semiallogeneic conceptus providing a secure niche for fetal development. Multiple mechanisms have evolved to prevent fetus-directed immune responses and alloreactive infiltration of the fetomaternal interface (1). These include creating a privileged local microenvironment that hampers T-cell priming and infiltration (2-4) but also imply global modulation of the immune system by pregnancy hormones and the shedding of fetal antigen into the mothers circulation (5).Intriguingly, pregnancy is also well known to suppress the inflammatory activity of a number of cell-mediated autoimmune diseases, including rheumatoid arthritis (6, 7), autoimmune hepatitis (8), and multiple sclerosis (MS) (9, 10). However, this beneficial effect is limited to the period of gestation and usually followed by a rebound of disease activity postpartum. In the case of MS, third trimester pregnancy leads to a remarkable reduction of the MS relapse rate (11), which exceeds the effects of most currently available disease-modifying drugs. Similarly, pregnancy as well as treatment with pregnancy hormones protect rodents from experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS (12) in both SJL/J and C57BL/6 mice (13-16), underpinning an interaction between pregnancy-related immune and endocrine adaptations and central nervous system (CNS) autoimmunity (17).The sensitive balance between conventional effector T cells (Tcons) and regulatory T cells (Tregs) has transpired as a common theme that connects reproductive biology and autoimmunity on a mechanistic level (18)(19)(20)(21). Tregs are characterized by the transcription factor forkhead box P3 (Foxp3) and effectively control effector responses mounted by Tcons in...

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Modern biology investigations on phytochromes as near-infrared fluorescent pigments pave the way for the development of new biosensors, as well as for optogenetics and in vivo imaging tools. Recently, near-infrared fluorescent proteins (NIR-FPs) engineered from biliverdin-binding bacteriophytochromes and cyanobacteriochromes, and from phycocyanobilin-binding cyanobacterial phytochromes have become promising probes for fluorescence microscopy and in vivo imaging. However, current NIR-FPs typically suffer from low fluorescence quantum yields and short fluorescence lifetimes. Here, we applied the rational approach of combining mutations known to enhance fluorescence in the cyanobacterial phytochrome Cph1 to derive a series of highly fluorescent variants with fluorescence quantum yield exceeding 15%. These variants were characterised by biochemical and spectroscopic methods, including time-resolved fluorescence spectroscopy. We show that these new NIR-FPs exhibit high fluorescence quantum yields and long fluorescence lifetimes, contributing to their bright fluorescence, and provide fluorescence lifetime imaging measurements in E.coli cells.