Biology subjects

Devlin, J. C.

Publications and source records attributed to Devlin, J. C..

9 recordsLinked to original sources

bioRxiv2026

Multiomics profiling of APECED peripheral blood highlights compositional increases in alternatively activated B cell subsets

APECED (Autoimmune PolyEndocrinopathy Candidiasis Ectodermal Dystrophy) is a rare syndrome of multi-organ autoimmunity driven by the presence of self-reactive T cells and autoantibodies caused by mutations in the gene Autoimmune regulator (AIRE). Compared to the well-defined role of AIRE in establishing and maintaining T cell central tolerance, less is known about how AIRE deficiency impacts B cell phenotypes that may contribute to a breakdown in peripheral B cell tolerance. Here we analyzed serum and peripheral blood cells from APECED patients and healthy donors using autoantibody profiling, proteomics, flow cytometry, scRNAseq based subset analysis, BCRseq, and autoantigen binding assays finding significant changes to the APECED B cell compartment. We show that while Naive and Transitional B cells are reduced, alternatively activated B cell subsets are expanded in APECED patients including IgM CD27+ and class switched Atypical B cells which exhibit BCR chain features prone to autoreactivity. Antibodies derived from either APECED or Healthy class switched atypical B cells bind autoantigens at significantly higher rates than control IgG B cells. Serum autoantibodies and proteomics highlight APECED common and patient variable changes. These results together show that APECED causes a compositional shift towards subsets that may promote broken B cell tolerance and autoimmunity.

immunology↗

bioRxiv2023

A role for BCL6 in maintaining CX3CR1+ CD4+ T cells during helminth infection

Distinct subsets of T lymphocytes express CX3CR1 under inflammatory conditions, but little is known about CX3CR1+ CD4+ T cells during Type 2 inflammation in helminth infections. Here, we used a fate-mapping mouse model to characterize CX3CR1+ CD4+ T cells during both acute Nippostrongylus brasiliensis and chronic Schistosoma mansoni helminth infections, revealing CX3CR1+ CD4+ T cells to be an activated tissue homing subset with varying capacity for cytokine production. Tracking these cells over time revealed that maintenance of CX3CR1 itself along with a TH2 phenotype conferred a survival advantage in the inflamed tissue. Single-cell RNA-sequencing analysis of fate-mapped CX3CR1+ CD4+ T cells from both the peripheral tissue and the spleen revealed a considerable level of diversity and identified a distinct population of BCL6+ TCF-1+ PD1+ CD4+ T cells in the spleen during helminth infections. Conditional deletion of BCL6 in CX3CR1+ cells result in fewer CX3CR1+ CD4+ during infection, indicating a role in sustaining CD4+ T cell responses to helminth infections. Overall, our studies revealed the behavior and heterogeneity of CX3CR1+ CD4+ T cells during Type 2 inflammation in helminth infections and identified BCL6 to be important in their maintenance.

immunology↗

bioRxiv2023

Single-cell analysis of CX3CR1+ cells reveal a pathogenic role for BIRC5+ myeloid proliferating cells driven by Staphylococcus aureus leukotoxins

Our previous studies identified a population of stem cell-like proliferating myeloid cells within inflamed tissues that could serve as a reservoir for tissue macrophages to adopt different activation states depending on the microenvironment. By lineage tracing cells derived from CX3CR1+ precursors in mice during infection and profiling by scRNA-seq, here we identify a cluster of BIRC5+ myeloid cells that expanded in the liver during either chronic infection with the parasite Schistosoma mansoni or the bacterial pathogen Staphylococcus aureus. In the absence of tissue damaging toxins, S. aureus infection does not elicit these BIRC5+ cells. Moreover, deletion of BIRC5 from CX3CR1 expressing cells results in improved survival during S. aureus infection. Hence, the combination of scRNA-Seq and genetic fate mapping CX3CR1+ cells revealed a toxin dependent pathogenic role for BIRC5 in myeloid cells during S. aureus infection.

immunology↗

bioRxiv2022

Clostridia isolated from helminth-colonized humans promote hatching of Trichuris muris

Soil transmitted intestinal worms known as helminths colonize over 1.5 billion people worldwide. Although helminth colonization has been associated with altered composition of the gut microbiota, such as increases in Clostridia, individual species have not been isolated and characterized. Here, we isolated and sequenced the genome of 13 Clostridia from the Orang Asli, an indigenous population in Malaysia with high prevalence of helminth infections. Metagenomic analysis of 650 fecal samples from urban and rural Malaysians revealed higher prevalence and abundance of these isolates compared to individuals in the United States, with Peptostreptococcaceae family members displaying a specific association with helminth colonization. Remarkably, Peptostreptococcaceae isolated from the Orang Asli displayed superior capacity to induce hatching of eggs from the murine helminth Trichuris muris. These findings support a model in which helminths select for gut colonization of microbes that in turn support their life cycle by promoting egg hatching.

microbiology↗

bioRxiv2020

Transcriptional Atlas of Ileal-Anal Pouch Immune Cells from Ulcerative Colitis Patients

How the human intestinal immune system is distinctly organized to respond to inflammation is still poorly understood. Here, we used single-cell RNA-sequencing to examine lamina propria CD45+ hematopoietic cells from patients with inflammatory bowel disease that have undergone ileal pouch-anal anastomosis, or the colon mucosa of ulcerative colitis patients. We identified a population of IL1B+ antimicrobial macrophages and FOXP3/+BATF+ T cells that are associated and expanded in inflamed tissues, which we further validated in other scRNA-seq datasets from IBD patients. CD8+ T cells were unexpectedly more abundant in the pouch than colon. Cell type specific markers obtained from single-cell RNA-sequencing was used to infer representation from bulk RNA sequencing datasets, which further implicated antimicrobial macrophages expressing IL1B with S100A8/A9 calprotectin as being associated with inflammation, as well as Bacteroides and Escherichia bacterial species. Finally, we find that non-responsiveness to anti-integrin biologic therapies in UC patients is associated with the signature of this antimicrobial macrophage population in a subset of patients. This study identified conserved and distinct features of intestinal inflammation between parts of the small and large intestine undergoing similar inflammation conditions.

immunology↗

bioRxiv2019

Distinct features of human myeloid cell cytokine response profiles identify neutrophil activation by cytokines as a prognostic feature during tuberculosis and cancer

Myeloid cells are a vital component of innate immunity and comprise of monocytes, macrophages, dendritic cells and granulocytes. How myeloid cell lineage affects activation states in response to cytokines remains poorly understood. The cytokine environment and cellular infiltrate during an inflammatory response may contain prognostic features that could predict disease outcome. Here we analyzed the transcriptional responses of human monocytes, macrophages, dendritic cells and neutrophils in response to stimulation by IFN-{gamma}, IFN-{beta} IFN-{lambda}, IL-4, IL-13 and IL-10 cytokines, to better understand the heterogeneity of activation states in inflammatory conditions. This generated a myeloid cell cytokine specific response matrix that can infer representation of myeloid cells and the cytokine environment they encounter during infection and in tumors. Neutrophils were highly responsive to type 1 and type 2 cytokine stimulation but did not respond to IL-10. We identified transcripts specific to IFN-{beta} stimulation, whereas other IFN signature genes were upregulated by both IFN-{gamma} and IFN-{beta}. When we used our matrix to deconvolute blood profiles from tuberculosis patients, the IFN-{beta} specific neutrophil signature was reduced in TB patients with active disease whereas the shared response to IFN-{gamma} and IFN-{beta} in neutrophils was increased. When applied to glioma patients, transcripts of neutrophils exposed to IL-4 or IL-13 and monocyte responses to IFN-{gamma} or IFN-{beta} emerged as opposing predictors of patient survival. Hence, by dissecting how different myeloid cells respond to cytokine activation, we can delineate biological roles for myeloid cells in different cytokine environments during disease processes, especially during infection and tumor progression.

immunology↗

bioRxiv2019

Housing laboratory mice in a natural environment uncovers genetic and environmental contributions to immune variation.

The relative contributions of genetic and environmental factors to variation in immune responses are still poorly understood. Here, we performed a deep phenotypic analysis of immunological parameters of laboratory mice released into an outdoor enclosure, carrying susceptibility genes (Nod2 and Atg16l1) implicated in the development of inflammatory bowel diseases. Variations of immune cell populations were largely driven by environment, whereas cytokine production in response to stimulation was affected more by genetic mutations. Multi-omic models identified transcriptional signatures associated with differences in T cell populations. Subnetworks associated with responses against Clostridium perfringens, Candida albicans and Bacteroides vulgatus were also coupled with rewilding. Hence, exposing laboratory mice carrying different genetic mutations to a natural environment uncovered important contributors to immune variation. One sentence summaryNatural environment exposure in laboratory mice primarily promotes variation in population frequencies of immune cells, whereas cytokine responses to stimulation are affected more by genetic susceptibility to inflammatory bowel disease.

immunology↗

bioRxiv2019

Altered immunity of laboratory mice in the natural environment is associated with fungal colonization

The immune systems of free-living mammals such as humans and wild mice display a heightened degree of activation compared with laboratory mice maintained under artificial conditions. Here, we demonstrate that releasing inbred laboratory mice into an outdoor enclosure to mimic life in a natural environment alters the state of immunity. In addition to enhancing the differentiation of T cell populations previously associated with pathogen exposure, we found that outdoor release of mice led to an increase in circulating granulocytes. However, rewilded mice were not infected by pathogens previously implicated in immune activation. Rather, changes to the immune system were associated with an altered composition of the microbiota, and fungi isolated from rewilded mice were sufficient to increase circulating granulocytes. These findings establish an experimental procedure to investigate the impact of the natural environment on immune development and identify a role for sustained fungal exposure in determining granulocyte numbers.

immunology↗

bioRxiv2018

Building a tumor atlas: integrating single-cell RNA-Seq data with spatial transcriptomics in pancreatic ductal adenocarcinoma

To understand tissue architecture it is necessary to understand both which cell types are present and their physical relationships to one another. Single-cell RNA-Seq (scRNA-Seq) has made significant progress towards the unbiased and systematic characterization of cell populations within a tissue by studying hundreds and thousands of cells in a single experiment. However, the characterization of the spatial organization of individual cells within a tissue has been more elusive. The recently introduced spatial transcriptomics method (ST) reveals the spatial pattern of gene expression within a tissue section at a resolution of a thousand 100 m spots across the tissue, each capturing the transcriptomes of [~]10-20 cells. Here, we present an approach for the integration of scRNA-Seq and ST data generated from the same sample of pancreatic cancer tissue. Using markers for cell types identified by scRNA-Seq, we robustly deconvolved the cell type composition of each ST spot to generate a spatial atlas of cell proportions across the tissue. Studying this atlas, we found that distinct spatial localizations accompany each of the cell populations that we identified. Our results provide a framework for creating a tumor atlas by mapping single-cell populations to their spatial region, as well as the inference of cell architecture in any tissue.

cancer biology↗