Biology subjects

Bossini-Castillo, L.

Publications and source records attributed to Bossini-Castillo, L..

5 recordsLinked to original sources

bioRxiv2026

Single-Cell RNA Sequencing Reveals Impaired Regulatory T Cell Function and a Pro-inflammatory Th17 Profile in Systemic Sclerosis

ObjectiveThis resource deeply characterizes the CD4+ T cell subpopulations populations in SSc patients, with a novel single-cell RNA sequencing (scRNA-seq) approach, offering unprecedented insights into the cellular and molecular underpinnings of the disease. MethodsWe performed scRNA-seq to analyze over 80,000 CD4+ T cells from 8 SSc patients and 8 healthy controls, integrating abundance, transcriptional, and TCR repertoire analysis, to define CD4+ T cell subtype-specific signatures associated with SSc. ResultsSSc CD4+ T cells displayed a global interferon-driven activation signature and significantly reduced TNF signaling. Key transcriptomic alterations included the downregulation of SOX4 and CD83, alongside an expansion of Th2 and proinflammatory, steroid-resistant Th17 cells. Furthermore, Tregs exhibited a destabilized state characterized by high FCRL3 and reduced FOXP3 expression. Finally, TCR repertoire analysis identified increased clonal expansion specifically within the central memory (Tcm) compartment. ConclusionTogether, this data revealed SSc-associated cell population states in CD4+ T cells with unique transcriptomic signatures and provided a publicly accessible interactive platform to facilitate exploration of this dataset by the research community.

genetics↗

bioRxiv2021

Immune disease risk variants regulate gene expression dynamics during CD4+ T cell activation

During activation, T cells undergo extensive changes in gene expression which shape the properties of cells to exert their effector function. Therefore, understanding the genetic regulation of gene expression during T cell activation provides essential insights into how genetic variants influence the response to infections and immune diseases. We generated a single-cell map of expression quantitative trait loci (eQTL) across a T cell activation time-course. We profiled 655,349 CD4+ naive and memory T cells, capturing transcriptional states of unstimulated cells and three time points of cell activation in 119 healthy individuals. We identified 38 cell clusters, including stable clusters such as central and effector memory T cells and transient clusters that were only present at individual time points of activation, such as interferon-responding cells. We mapped eQTLs using a T cell activation trajectory and identified 6,407 eQTL genes, of which a third (2,265 genes) were dynamically regulated during T cell activation. We integrated this information with GWAS variants for immune-mediated diseases and observed 127 colocalizations, with significant enrichment in dynamic eQTLs. Immune disease loci colocalized with genes that are involved in the regulation of T cell activation, and genes with similar functions tended to be perturbed in the same direction by disease risk alleles. Our results emphasize the importance of mapping context-specific gene expression regulation, provide insights into the mechanisms of genetic susceptibility of immune diseases, and help prioritize new therapeutic targets.

genomics↗

bioRxiv2019

Immune disease variants modulate gene expression in regulatory CD4+ T cells and inform drug targets

Identifying cellular functions dysregulated by disease associated variants could implicate novel pathways for drug targeting or modulation in cell therapies. Variants associated with immune diseases point towards the role of CD4+ regulatory T cells (Tregs), cell type critical for immune homeostasis. To translate the effects of immune disease alleles on Treg function we mapped genetic regulation (QTL) of gene expression and chromatin activity in Tregs. We identified 123 loci where Treg QTLs colocalized with immune disease variants. These colocalizations indicated that dysregulation of key Treg pathways, including cell activation via CD28 and IL-2 signalling mediated by STAT5A contribute to the shared pathobiology of immune diseases. Finally, using disease GWAS signals colocalizing with Treg QTLs, we identified 34 known drug targets and 270 targets with drug tractability evidence. Our study is the first in-depth characterization of immune disease variant effects on Treg gene expression modulation and dysregulation of Treg function.

genetics↗

bioRxiv2019

Chromatin activity at GWAS loci identifies T cell states driving complex immune diseases

Complex immune disease variants are enriched in active chromatin regions of T cells and macrophages. However, whether these variants function in specific cell states or stages of cell activation is unknown. We stimulated T cells and macrophages in the presence of thirteen different cytokine cocktails linked to immune diseases and profiled active enhancers and promoters together with regions of open chromatin. We observed that T cell activation induced major chromatin remodelling, while additional exposure to cytokines fine-tuned the magnitude of these changes. Therefore, we developed a new statistical method that accounts for subtle changes in chromatin landscape to identify SNP enrichment across cell states. Our results point towards the role of immune disease variants in early rather than late activation of memory CD4+ T cells, and with limited differences across polarizing cytokines. Furthermore, we demonstrate that inflammatory bowel disease variants are enriched in chromatin regions active in Th1 cells, while asthma variants overlap regions active in Th2 cells. We also show that Alzheimers disease variants are enriched in different macrophage cell states. Our results represent the first in-depth analysis of immune disease variants across a comprehensive panel of activation states of T cells and macrophages.

genetics↗

bioRxiv2017

A Balance Between Regulatory Constraints And Pathogen Pressure Shapes The Evolution Of Innate Immunity

As the first line of defence against pathogens, cells mount an innate immune response, which is highly variable from cell to cell. The response must be potent yet carefully controlled to avoid self-damage. How these constraints have shaped the evolution of innate immunity remains poorly understood. Here, we characterise this programmes transcriptional divergence between species and expression variability across cells. Using bulk and single-cell transcriptomics in primate and rodent fibroblasts challenged with an immune stimulus, we reveal a striking architecture of the innate immune response. Rapidly diverging genes, including cytokines and chemokines, also vary across cells and have distinct promoter structures. Conversely, genes involved in response regulation, such as transcription factors and kinases, are conserved between species and display low cell-to-cell variability. We suggest that this unique expression pattern, observed across species and conditions, has evolved as a mechanism for fine-tuned regulation, to achieve an effective but balanced response.

evolutionary biology↗