Biology subjects

Maurer, K.

Publications and source records attributed to Maurer, K..

5 recordsLinked to original sources

bioRxiv2024

TNFSF13 insufficiency disrupts human colonic epithelial cell-mediated B cell differentiation

Cytokines mediating epithelial and immune cell interactions modulate mucosal healing-a process that goes awry with chronic inflammation as in inflammatory bowel disease. TNFSF13 is a cytokine important for B cell maturation and function, but roles for epithelial TNFSF13 and putative contribution to inflammatory bowel disease are poorly understood. We evaluated functional consequences of a novel monoallelic TNFSF13 variant using biopsies, tissue-derived colonoids and induced pluripotent stem cell (iPSC)-derived colon organoids. TNFSF13 variant colonoids exhibited a >50% reduction in secreted TNFSF13, increased epithelial proliferation, and reduced apoptosis, which was confirmed in iPSC-derived colon organoids. Single cell RNA-sequencing, flow cytometry, and co-immunoprecipitation identified FAS as the predominant colonic epithelial receptor for TNFSF13. Imaging mass cytometry revealed an increase in epithelial-associated B cells in TNFSF13 variant colon tissue sections. Finally, TNFSF13 variant colonoids co-cultured with memory B cells demonstrated a reduction in the production of IgA+ plasma cells compared to control colonoid co-cultures. Our findings support a role for epithelial TNFSF13 as a regulator of colonic epithelial growth and epithelial crosstalk with B cells. SUMMARYEpithelial TNFSF13 regulates colonic epithelial growth and epithelial-B cell interactions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/614260v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1e5b892org.highwire.dtl.DTLVardef@b8857forg.highwire.dtl.DTLVardef@448b95org.highwire.dtl.DTLVardef@2820e2_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Coordinated Immune Cell Networks in the Bone Marrow Microenvironment Define the Graft versus Leukemia Response with Adoptive Cellular Therapy

Understanding how intra-tumoral immune populations coordinate to generate anti-tumor responses following therapy can guide precise treatment prioritization. We performed systematic dissection of an established adoptive cellular therapy, donor lymphocyte infusion (DLI), by analyzing 348,905 single-cell transcriptomes from 74 longitudinal bone-marrow samples of 25 patients with relapsed myeloid leukemia; a subset was evaluated by protein-based spatial analysis. In acute myelogenous leukemia (AML) responders, diverse immune cell types within the bone-marrow microenvironment (BME) were predicted to interact with a clonally expanded population of ZNF683+GZMB+ CD8+ cytotoxic T lymphocytes (CTLs) which demonstrated in vitro specificity for autologous leukemia. This population, originating predominantly from the DLI product, expanded concurrently with NK and B cells. AML nonresponder BME revealed a paucity of crosstalk and elevated TIGIT expression in CD8+ CTLs. Our study highlights recipient BME differences as a key determinant of effective anti-leukemia response and opens new opportunities to modulate cell-based leukemia-directed therapy.

cancer biology↗

bioRxiv2023

DIISCO: A Bayesian framework for inferring dynamic intercellular interactions from time-series single-cell data

Characterizing cell-cell communication and tracking its variability over time is essential for understanding the coordination of biological processes mediating normal development, progression of disease, or responses to perturbations such as therapies. Existing tools lack the ability to capture time-dependent intercellular interactions, such as those influenced by therapy, and primarily rely on existing databases compiled from limited contexts. We present DIISCO, a Bayesian framework for characterizing the temporal dynamics of cellular interactions using single-cell RNA-sequencing data from multiple time points. Our method uses structured Gaussian process regression to unveil time-resolved interactions among diverse cell types according to their co-evolution and incorporates prior knowledge of receptor-ligand complexes. We show the interpretability of DIISCO in simulated data and new data collected from CAR-T cells co-cultured with lymphoma cells, demonstrating its potential to uncover dynamic cell-cell crosstalk. AvailabilityDIISCO is publicly accessible at https://github.com/azizilab/DIISCO_public. All data will be deposited to GEO upon publication.

bioinformatics↗

bioRxiv2022

Latent human herpesvirus 6 is reactivated in chimeric antigen receptor T cells

Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are still being understood. For example, we currently lack a comprehensive understanding of the mechanisms of neurotoxicity observed in patients receiving T cell therapies, including recent reports of encephalitis caused by human herpesvirus 6 (HHV-6) reactivation1. Here, via petabase-scale viral RNA data mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in human CD4+ T cells in standard in vitro cultures. Using single-cell sequencing, we identify a rare population of HHV-6 super-expressors (~1 in 300-10,000 cells) that possess high viral transcriptional activity in chimeric antigen receptor (CAR) T cell culture before spreading to infect other cells in vitro. Through the analysis of single-cell sequencing data from patients receiving cell therapy products that are FDA-approved2 or used in clinical studies3,4, we identify the presence of CAR+, HHV-6 super-expressor T cells in vivo. Together, our study implicates cell therapy products as a source of lytic HHV-6 reported in clinical trials1,5-7 and has broad implications for the design, production, and monitoring of cell therapies.

immunology↗

bioRxiv2019

Mutation of an L-Type Calcium Channel Gene Leads to a Novel Human Primary Cellular Immunodeficiency

Human primary immunodeficiencies are inherited diseases that can provide valuable insight into the immune system. Calcium (Ca2+) is a vital secondary messenger in T lymphocytes regulating a vast array of important events including maturation, homeostasis, activation, and apoptosis and can enter the cell through CRAC, TRP, and Cav channels. Here we describe three Cav1.4-deficient siblings presenting with X-linked incomplete congenital stationary night blindness as well as an immune phenotype characterized by several recurrent infections. Complete exome sequencing demonstrated that the patients share only a single pathogenic allele; a R625X (p.Arg625Ter) point mutation that leads to a premature stop codon in the CACNA1F gene encoding the L-type Ca2+ channel Cav1.4. The subjects uniformly exhibited an expansion of central and effector memory T lymphocytes, and evidence of T lymphocytes exhaustion with corresponding upregulation of inhibitory receptors. Moreover, the sustained elevated levels of activation markers on B lymphocytes suggest that they are in a chronic state of activation. Finally, the T lymphocytes from patients and CACNA1F knockdown Jurkat T lymphocytes exhibited a reduced Ca2+ flux, compared to controls. This is the first example where the mutation of any Cav channel causes a primary immunodeficiency in humans and establishes the physiological importance of Cav channels in the human immune system.

immunology↗