Biology subjects

Cunningham-Rundles, C.

Publications and source records attributed to Cunningham-Rundles, C..

6 recordsLinked to original sources

bioRxiv2024

NF-κB Signaling is Required for X-Chromosome Inactivation Maintenance Following T cell Activation

X Chromosome Inactivation (XCI) is a female-specific process which balances X-linked gene dosage between sexes. Unstimulated T cells lack cytological enrichment of Xist RNA and heterochromatic modifications on the inactive X chromosome (Xi), and these modifications become enriched at the Xi after cell stimulation. Here, we examined allele-specific gene expression and the epigenomic profiles of the Xi following T cell stimulation. We found that the Xi in unstimulated T cells is largely dosage compensated and is enriched with the repressive H3K27me3 modification, but not the H2AK119-ubiquitin (Ub) mark, even at promoters of XCI escape genes. Upon CD3/CD28-mediated T cell stimulation, the Xi accumulates H2AK119-Ub and H3K27me3 across the Xi. Next, we examined the T cell signaling pathways responsible for Xist RNA localization to the Xi and found that T cell receptor (TCR) engagement, specifically NF-{kappa}B signaling downstream of TCR, is required. Disruption of NF-{kappa}B signaling, using inhibitors or genetic deletions, in mice and patients with immunodeficiencies prevents Xist/XIST RNA accumulation at the Xi and alters expression of some X-linked genes. Our findings reveal a novel connection between NF-{kappa}B signaling pathways which impact XCI maintenance in female T cells.

immunology↗

bioRxiv2024

A Germinal Center Checkpoint of AIRE in B Cells LimitsAntibody Diversification

In response to antigens, B cells undergo antibody diversification, including affinity maturation and class switching, mediated by activation-induced cytidine deaminase (AID) in secondary lymphoid organs, but uncontrolled AID activity can precipitate autoimmunity and cancer. The regulation of antibody diversification is of fundamental importance, though the mechanisms underlying these pathways are not well understood. We found that autoimmune regulator (AIRE), the molecule essential for T cell tolerance, is expressed in germinal center (GC) B cells in a CD40-dependent manner, interacts with AID and negatively regulates antibody affinity maturation and class switching by inhibiting AID function. AIRE deficiency in B cells caused altered antibody repertoire, increased somatic hypermutations, elevated autoantibodies to T helper 17 effector cytokines and defective control of skin Candida albicans. These results define a GC B cell checkpoint of humoral immunity and illuminate new approaches of generating high-affinity neutralizing antibodies for immunotherapy.

immunology↗

bioRxiv2023

Atypical memory B cells form a pre-plasmacellular reservoir for steady-state IgD responses to common nasopharyngeal antigens

The human nasopharyngeal mucosa includes organized lymphoepithelial structures continually engaged in frontline immune responses to aerodigestive antigens. Advancing our understanding of these responses might lead to the development of new strategies for the prevention and treatment of common immune disorders such as allergies. Here we identified a hitherto elusive tonsillar subset of atypical IgD class-switched IgD+IgM- memory (IgD-ME) B cells that were clonally related to IgD+IgM- germinal center (IgD-GC) B cells and IgD-secreting IgD+IgM- plasma cells (IgD-PCs) but not anergic IgD+IgM- B cells. Consistent with their pre-plasmacellular properties, IgD-ME B cells served as preferential precursors of IgD-PCs over IgD-GC B cells. IgD antibodies from IgD+IgM- cells acquired reactivity to multiple oral, airborne and commensal antigens through a mutation-dependent pathway involving both innate and adaptive signals. Thus, IgD-ME B cells may form a ready-to-use pre-plasmacellular reservoir for steady-state IgD responses likely aimed at enhancing nasopharyngeal homeostasis. One Sentence SummaryTonsillar atypical memory B cells form a ready-to-use pre-plasmacellular repertoire for IgD responses to common aerodigestive antigens.

immunology↗

bioRxiv2022

Disease diagnostics using machine learning of immune receptors

Clinical diagnosis typically incorporates physical examination, patient history, and various laboratory tests and imaging studies, but makes limited use of the human systems own record of antigen exposures encoded by receptors on B cells and T cells. We analyzed immune receptor datasets from 593 individuals to develop MAchine Learning for Immunological Diagnosis (Mal-ID), an interpretive framework to screen for multiple illnesses simultaneously or precisely test for one condition. This approach detects specific infections, autoimmune disorders, vaccine responses, and disease severity differences. Human-interpretable features of the model recapitulate known immune responses to SARS-CoV-2, Influenza, and HIV, highlight antigen-specific receptors, and reveal distinct characteristics of Systemic Lupus Erythematosus and Type-1 Diabetes autoreactivity. This analysis framework has broad potential for scientific and clinical interpretation of human immune responses.

immunology↗

bioRxiv2021

Gut IgA Enhances Systemic IgG Responses to Pneumococcal Vaccines Through the Commensal Microbiota

The gut microbiota enhances systemic immunoglobulin G (IgG) responses to vaccines. However, it is unknown whether this effect involves IgA, a mucosal antibody that coats intestinal microbes. Here we found that gut IgA increased peripheral IgG responses to pneumococcal vaccines, as these responses were profoundly impaired in mice with global or mucosa-restricted IgA deficiency. The positive effect of IgA on vaccine-induced IgG production implicated gut bacteria. Indeed, IgG responses to pneumococcal vaccines were also defective in ex-germ free mice recolonized with gut microbes from mouse or human IgA-deficient donors. IgA exerted this IgG-enhancing effect by constraining the systemic translocation of intestinal commensal antigens, which caused chronic immune activation, including T cell overexpression of programmed death-1. This immune inhibitory receptor hindered vaccine-specific IgG production by eliciting functional B cell unresponsiveness, which was reverted by anti-programmed death-1 treatment. Thus, gut IgA is functionally interconnected with systemic IgG via intestinal microbes.

immunology↗

bioRxiv2017

Ruxolitinib partially reverses functional NK cell deficiency in patients with STAT1 gain-of-function mutations

BackgroundNatural Killer (NK) cells are critical innate effector cells whose development is dependent on the JAK-STAT pathway. NK deficiency can result in severe or refractory viral infections. Patients with Signal Transducer and Activator of Transcription (STAT)1 gain of function (GOF) mutations have increased viral susceptibility.\n\nObjectiveWe sought to investigate NK cell function in STAT1 GOF patients. Methods: NK cell phenotype and function were determined in 16 STAT1 GOF patients.\n\nMethodsNK cell phenotype and function were determined in 16 STAT1 GOF patients.NK cell lines expressing patient mutations were generated with CRISPR-Cas9 mediated gene editing. STAT1 GOF NK cells were treated in vitro with ruxolitinib.\n\nResultsPeripheral blood NK cells from of STAT1 GOF patients had impaired terminal maturation. Specifically, patients with STAT1 GOF mutations have immature CD56dim NK cells with decreased expression of CD16, perforin, CD57 and impaired cytolytic function. STAT1 phosphorylation was elevated but STAT5 was aberrantly phosphorylated in response to IL-2 stimulation. Upstream inhibition of STAT signaling with the small molecule JAK1/2 inhibitor ruxolitinib in vitro and in vivo restored perforin expression in CD56dim NK cells and partially restored NK cell cytotoxic function.\n\nConclusionsProperly regulated STAT1 signaling is critical for NK cell maturation and function. Modulation of elevated STAT1 phosphorylation with ruxolitinib is an important option for therapeutic intervention in patients with STAT1 GOF mutations.

immunology↗