Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing-remitting disease course at early stages, distinct lesion characteristics in cortical gray versus subcortical white matter, and neurodegeneration at chronic stages. We assessed multilineage cell expression changes using single-nucleus RNA sequencing (snRNA-seq) and validated results using multiplex in situ hybridization in MS lesions. We found selective vulnerability and loss of excitatory CUX2 -expressing projection neurons in upper cortical layers underlying meningeal inflammation; such MS neuron populations showed upregulation of stress pathway genes and long non-coding RNAs. Signatures of stressed oligodendrocytes, reactive astrocytes and activated phagocytosing cells mapped most strongly to the rim of MS plaques. Interestingly, snRNA-seq identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. Our findings indicate lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation contributing to MS lesion progression.

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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While a link between inflammation and the development of neuropsychiatric disorders, including major depressive disorder (MDD) is supported by a growing body of evidence, little is known about the contribution of aberrant adaptive immunity in this context. Here, we conducted in-depth characterization of T cell phenotype and T cell receptor (TCR) repertoire in MDD. For this cross-sectional case–control study, we recruited antidepressant-free patients with MDD without any somatic or psychiatric comorbidities (n = 20), who were individually matched for sex, age, body mass index, and smoking status to a non-depressed control subject (n = 20). T cell phenotype and repertoire were interrogated using a combination of flow cytometry, gene expression analysis, and next generation sequencing. T cells from MDD patients showed significantly lower surface expression of the chemokine receptors CXCR3 and CCR6, which are known to be central to T cell differentiation and trafficking. In addition, we observed a shift within the CD4+ T cell compartment characterized by a higher frequency of CD4+CD25highCD127low/− cells and higher FOXP3 mRNA expression in purified CD4+ T cells obtained from patients with MDD. Finally, flow cytometry-based TCR Vβ repertoire analysis indicated a less diverse CD4+ T cell repertoire in MDD, which was corroborated by next generation sequencing of the TCR β chain CDR3 region. Overall, these results suggest that T cell phenotype and TCR utilization are skewed on several levels in patients with MDD. Our study identifies putative cellular and molecular signatures of dysregulated adaptive immunity and reinforces the notion that T cells are a pathophysiologically relevant cell population in this disorder.

Background: Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), can be suppressed in its early stages but eventually becomes clinically progressive and unresponsive to therapy. Here, we investigate whether the therapeutic resistance of progressive MS can be attributed to chronic immune cell accumulation behind the blood-brain barrier (BBB). Methods: We systematically track CNS-homing immune cells in the peripheral blood of 31 MS patients and 31 matched healthy individuals in an integrated analysis of 497,705 single-cell transcriptomes and 355,433 surface protein profiles from 71 samples. Through spatial RNA sequencing, we localize these cells in post mortem brain tissue of 6 progressive MS patients contrasted against 4 control brains (20 samples, 85,000 spot transcriptomes). Findings: We identify a specific pathogenic CD161+/lymphotoxin beta (LTB)+ T cell population that resides in brains of progressive MS patients. Intriguingly, our data suggest that the colonization of the CNS by these T cells may begin earlier in the disease course, as they can be mobilized to the blood by usage of the integrin-blocking antibody natalizumab in relapsing-remitting MS patients. Conclusions: As a consequence, we lay the groundwork for a therapeutic strategy to deplete CNS-homing T cells before they can fuel treatment-resistant progression.

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Problem Steroid hormones such as progesterone and glucocorticoids rise during pregnancy and are accountable for the adaptation of the maternal immune system to pregnancy. How steroid hormones induce fetal tolerance is not fully understood. We hypothesized that steroid hormones selectively regulate the T‐cell response by promoting T‐cell death. Method of study We incubated murine spleen cells isolated from non‐pregnant and pregnant mice with physiological concentrations of steroid hormones in vitro and analyzed T‐cell subsets after 48 h of incubation. ResultsWe found that progesterone and the synthetic glucocorticoid dexamethasone induce T‐cell death. CD4+ regulatory T (Treg) cells were refractory toward progesterone‐induced cell death, in contrast to conventional CD4+ T cells, which resulted in a preferential enrichment of CD4+ Tregcells in culture. T cells isolated from pregnant mice at early and late gestation showed comparable sensitivity to steroid‐induced cell death. The target receptor for progesterone in immune cells is controversially discussed. We provide here support of progesterone binding to the glucocorticoid receptor as only T cells lacking the glucocorticoid but not the progesterone receptor showed resistance against progesterone‐induced death. ConclusionsOur results indicate that high levels of progesterone during pregnancy can induce selective T‐cell death by binding the glucocorticoid receptor. Although physiological hormone concentrations were used, due to different bioavailability of steroid hormones in vivo these results have to be validated in an in vivo model. This mechanism might ensure immunological tolerance at the feto‐maternal interface at gestation.