Breaking tolerance: an update of Treg dysfunction in autoimmunity.

FOXP3 regulatory T cells (Tregs) are essential for maintaining immune tolerance, and their dysfunction is a hallmark of autoimmune diseases. Recent studies have identified key transcriptional, metabolic, and environmental drivers of Treg instability and loss of function. Understanding these mechanisms opens new avenues for therapeutic interventions aimed at restoring immune homeostasis in autoimmunity.

Inflamed Microglia like Macrophages in the Central Nervous System of Prodromal Parkinson's Disease.

We investigated the role of inflammation in the pathogenesis of prodromal Parkinson's Disease (PD), performing single-cell RNAseq analysis of cerebrospinal fluid (CSF) and blood from 111 individuals, comparing control subjects with early prodromal PD and later PD to patients with multiple sclerosis (MS). Surprisingly, we identified a pleocytosis in the CSF, most pronounced in patients with early PD. Single-cell RNAseq revealed increases in CSF-specific microglia-like macrophages expressing JAK-STAT and TNFα signaling signatures in prodromal PD, with a lack of T cell activation in the CSF.

Latent EBV enhances the efficacy of anti-CD3 mAb in Type 1 diabetes.

Teplizumab is approved for delaying the diagnosis of type 1 diabetes by modulating progression of disease. Compared to EBV-seronegative patients, those who are EBV-seropositive prior to treatment have a more robust response to teplizumab in two clinical trials. Here we compare the phenotypes, transcriptomes and development of peripheral blood cells before and after teplizumab treatment in participants.

Transcriptomic profiling after B cell depletion reveals central and peripheral immune cell changes in multiple sclerosis.

Multiple sclerosis (MS) is a complex, genetically mediated autoimmune disease of the CNS, in which anti-CD20-mediated B cell depletion is remarkably effective in the treatment of early disease. Although previous studies investigated the effect of B cell depletion on select immune cell subsets using flow cytometry-based methods, the therapeutic effect on the patient's immune landscape is unknown. In this study, we explored how B cell-depleting therapies modulate the immune landscape using single-cell RNA-Seq.

Cholesterol promotes mRNA expression in CD4 effector/memory cells by SGK1 activation.

IFNγ-secreting T cells are central for the maintenance of immune surveillance within the central nervous system (CNS). It was previously reported in healthy donors that the T-cell environment in the CNS induces distinct signatures related to cytotoxic capacity, CNS trafficking, tissue adaptation, and lipid homeostasis. These findings suggested that the CNS milieu consisting predominantly of lipids mediated the metabolic conditions leading to IFNγ-secreting brain CD4 T cells.

A Nerve-Fibroblast Axis in Mammalian Lung Fibrosis.

Fibrosis contributes to incurable pathologies in vital organs including the lung. Myofibroblasts are fibrogenic effector cells that accumulate via incompletely understood mechanisms. We discovered that α1-adrenoreceptor expressing myofibroblasts receive sympathetic nerve-derived noradrenergic inputs in fibrotic mouse and human lungs.

An autoimmune transcriptional circuit drives FOXP3 regulatory T cell dysfunction.

Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4FOXP3 regulatory T cells (T) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of T in the autoimmune disease multiple sclerosis (MS) to identify critical transcriptional programs regulating human autoimmunity.

Single-Cell Profiling Reveals Immune Aberrations in Progressive Idiopathic Pulmonary Fibrosis.

Changes in peripheral blood cell populations have been observed, but not detailed, at single-cell resolution in idiopathic pulmonary fibrosis (IPF). We sought to provide an atlas of the changes in the peripheral immune system in stable and progressive IPF. Peripheral blood mononuclear cells (PBMCs) from patients with IPF and control subjects were profiled using 10× chromium 5' single-cell RNA sequencing.

The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases.

The discovery of FOXP3 regulatory T (T) cells as a distinct cell lineage with a central role in regulating immune responses provided a deeper understanding of self-tolerance. The transcription factor FOXP3 serves a key role in T cell lineage determination and maintenance, but is not sufficient to enable the full potential of T cell suppression, indicating that other factors orchestrate the fine-tuning of T cell function. Moreover, FOXP3-independent mechanisms have recently been shown to contribute to T cell dysfunction.

Systems Analysis of Immune Changes after B-cell Depletion in Autoimmune Multiple Sclerosis.

Multiple sclerosis (MS) is a complex genetically mediated autoimmune disease of the central nervous system where anti-CD20-mediated B cell depletion is remarkably effective in the treatment of early disease. While previous studies investigated the effect of B cell depletion on select immune cell subsets using flow cytometry-based methods, the therapeutic impact on patient immune landscape is unknown. In this study, we explored how a therapy-driven " " modulates the diverse immune landscape by measuring transcriptomic granularity with single-cell RNA sequencing (scRNAseq).

Peripheral Blood Single-Cell Sequencing Uncovers Common and Specific Immune Aberrations in Fibrotic Lung Diseases.

Rationale And Objectives: The extent and commonality of peripheral blood immune aberrations in fibrotic interstitial lung diseases are not well characterized. In this study, we aimed to identify common and distinct immune aberrations in patients with idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (FHP) using cutting-edge single-cell profiling technologies.

Methods: Single-cell RNA sequencing was performed on patients and healthy controls' peripheral blood and bronchoalveolar lavage samples using 10X Genomics 5' gene expression and V(D)J profiling.

Latent EBV impairs immune cell signaling and enhances the efficacy of anti-CD3 mAb in Type 1 Diabetes.

Teplizumab has been approved for the delay of the onset of type 1 diabetes and may modulate new onset disease. We found that patients who were EBV positive at baseline had a more robust response to drug in two clinical trials and therefore postulated that latent virus has general effects in modifying immune responses. We compared the phenotypes, transcriptomes, and development of peripheral blood cells before and after teplizumab treatment.

Regulatory T cells in peripheral tissue tolerance and diseases.

Maintenance of peripheral tolerance by CD4Foxp3 regulatory T cells (Tregs) is essential for regulating autoreactive T cells. The loss of function of Foxp3 leads to autoimmune disease in both animals and humans. An example is the rare, X-linked recessive disorder known as IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy X-linked) syndrome.

Single-cell profiling reveals immune aberrations in progressive idiopathic pulmonary fibrosis.

Rationale: Changes in peripheral blood cell populations have been observed but not detailed at single-cell resolution in idiopathic pulmonary fibrosis (IPF).

Objectives: To provide an atlas of the changes in the peripheral immune system in stable and progressive IPF.

Methods: Peripheral blood mononuclear cells (PBMCs) from IPF patients and controls were profiled using 10x Chromium 5' single-cell RNA sequencing (scRNA-seq).

Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine-associated myocarditis.

Rare immune-mediated cardiac tissue inflammation can occur after vaccination, including after SARS-CoV-2 mRNA vaccines. However, the underlying immune cellular and molecular mechanisms driving this pathology remain poorly understood. Here, we investigated a cohort of patients who developed myocarditis and/or pericarditis with elevated troponin, B-type natriuretic peptide, and C-reactive protein levels as well as cardiac imaging abnormalities shortly after SARS-CoV-2 mRNA vaccination.

Hyperosmotic stress response regulates interstitial homeostasis and pathogenic inflammation.

Hyperosmotic stress triggers an evolutionally preserved, fundamental cellular response. A growing body of evidence has highlighted the role of extra-renal, interstitial hyperosmolality in maintaining local tissue immune homeostasis and potentially driving tissue inflammation in human diseases. The hyperosmotic stress response initiates cellular shrinkage, oxidative stress, metabolic remodeling and cell cycle arrest, all of which are adjusted by a counteractive adaptative response that includes osmolyte synthesis, upregulation of ion transporters and induction of heat shock proteins.

PD-1CXCR5CD4 peripheral helper T cells promote CXCR3 plasmablasts in human acute viral infection.

T cell-B cell interaction is the key immune response to protect the host from severe viral infection. However, how T cells support B cells to exert protective humoral immunity in humans is not well understood. Here, we use COVID-19 as a model of acute viral infections and analyze CD4 T cell subsets associated with plasmablast expansion and clinical outcome.

A multiple sclerosis-protective coding variant reveals an essential role for HDAC7 in regulatory T cells.

Genome-wide association studies identifying hundreds of susceptibility loci for autoimmune diseases indicate that genes active in immune cells predominantly mediate risk. However, identification and functional characterization of causal variants remain challenging. Here, we focused on the immunomodulatory role of a protective variant of histone deacetylase 7 (HDAC7).

Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis.

B cell depletion in patients with relapsing-remitting multiple sclerosis (RRMS) markedly prevents new MRI-detected lesions and disease activity, suggesting the hypothesis that altered B cell function leads to the activation of T cells driving disease pathogenesis. Here, we performed comprehensive analyses of CD40 ligand- (CD40L-) and IL-21-stimulated memory B cells from patients with MS and healthy age-matched controls, modeling the help of follicular helper T cells (Tfh cells), and found a differential gene expression signature in multiple B cell pathways. Most striking was the impaired TIGIT expression on MS-derived B cells mediated by dysregulation of the transcription factor TCF4.

Identity thieves: T cells steal CD20 from B cells but mark themselves for certain death.

T cells can acquire CD20 from B cells via trogocytosis, then contribute to autoimmune neurological disease while becoming targets for therapeutically effective B cell depletion.

Type I interferon transcriptional network regulates expression of coinhibitory receptors in human T cells.

Although inhibition of T cell coinhibitory receptors has revolutionized cancer therapy, the mechanisms governing their expression on human T cells have not been elucidated. In the present study, we show that type 1 interferon (IFN-I) regulates coinhibitory receptor expression on human T cells, inducing PD-1/TIM-3/LAG-3 while inhibiting TIGIT expression. High-temporal-resolution mRNA profiling of IFN-I responses established the dynamic regulatory networks uncovering three temporal transcriptional waves.

Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19.

Dysregulated immune responses against the SARS-CoV-2 virus are instrumental in severe COVID-19. However, the immune signatures associated with immunopathology are poorly understood. Here we use multi-omics single-cell analysis to probe the dynamic immune responses in hospitalized patients with stable or progressive course of COVID-19, explore V(D)J repertoires, and assess the cellular effects of tocilizumab.