Biology subjects

Brand, E. C.

Publications and source records attributed to Brand, E. C..

4 recordsLinked to original sources

bioRxiv2025

Clonal overlap and convergent clustering of T-cell receptor signatures in Crohn's disease in monozygotic twins

IntroductionThe dysregulated immune-response in Crohns disease might result from disturbances in the T-cell receptor (TCR) repertoire. To investigate this hypothesis, we compared the peripheral TCR repertoire within T-cell subsets in twin pairs, concordant and discordant for Crohns disease. MethodsWe performed TCR and TCR{beta} sequencing on peripheral flow-sorted CD4+ memory gut- homing (integrin4{beta}7+), non-gut-homing (integrin4{beta}7-), and regulatory T-cells (Tregs) from Dutch monozygotic Crohns disease concordant twins (N=8), monozygotic Crohns disease discordant twins (N=8), and healthy controls (N=4). TCR diversity and clonality, overlap between individuals, convergence and enrichment, and clustering of the TCR repertoire was studied and compared to previously reported Crohns disease-related TCRs. ResultsOverall diversity and clonality was comparable between Crohns disease patients, healthy cotwins and healthy controls. Comparing T-cell subsets, a decreased diversity and increased clonality was observed for Tregs. Concordant Crohns disease twins had an increased overlap in TCRs for Tregs and CD4+ memory gut-homing T-cells. Using TCR convergence, enrichment and subsequent clustering analyses, we identified eight clusters of TCRs potentially related with Crohns disease. The identified Crohns disease-related TCR signatures have not previously been described in relation to Crohns disease, and have thus far mostly unknown antigen specificity. ConclusionsIncreased overlap in the TCR repertoires of monozygotic twin pairs concordant for Crohns disease suggest that (antigen-driven) skewing of the TCR repertoire could play a role in the pathophysiology of Crohns disease. The identified TCR-based Crohns disease signatures are prime targets for further study into the pathogenesis of Crohns disease.

immunology↗

bioRxiv2025

T cell-microbiome associations captured through T cell receptor convergence analysis

The gut microbiome modulates mucosal immunity, yet how specific bacterial taxa shape the diversity and specificity of T cell receptor (TCR) repertoires remains poorly understood. Existing approaches emphasize single-species effects or broad immune features, without pinpointing which microbes drive specific T cell clonotypes. We present AIRRWAS, a computational framework that integrates TCR-microbiome interaction analysis with targeted in vitro validation to detect genus-level TCR convergence. Applied to three independent cohorts, AIRRWAS identified reproducible associations between convergent TCR clusters and 21 bacterial genera spanning core commensals, probiotics and taxa with immunomodulatory roles. Predicted clonotypes were enriched within the TCR-microbiome interaction network and preferentially activated by genus-matched stimuli, eliciting different functional T cell responses. These findings demonstrate that distinct repertoires can share genus-specific TCR motifs, enabling detection of shared immune signatures. AIRRWAS can map these TCR- microbiome interactions, laying the groundwork for biomarker discovery immune monitoring and the development of microbiome-targeted therapies.

bioinformatics↗

bioRxiv2022

Compartment-driven imprinting of intestinal CD4 (regulatory) T cells in inflammatory bowel disease and homeostasis

ObjectiveThe mucosal immune system is implicated in the etiology and progression of inflammatory bowel diseases. The lamina propria and epithelium of the gut mucosa constitute two separate compartments, containing distinct T cell populations. Human CD4 T cell programming and regulation of lamina propria and epithelium CD4 T cells, especially during inflammation, remains incompletely understood. DesignWe performed imaging mass cytometry, flow cytometry, bulk and single-cell RNA-sequencing to profile ileal lamina propria and intraepithelial CD4 T cells (CD4CD8, regulatory T cells (Tregs), CD69- and CD69high Trm T cells) in controls and Crohns disease (CD) patients (paired non-inflamed and inflamed). ResultsInflammation results in alterations of the CD4 T cell population with a pronounced increase in Tregs and migrating/infiltrating cells. On a transcriptional level, inflammation within the epithelium induced T cell activation, increased IFN{gamma} responses and effector Treg differentiation. Conversely, few transcriptional changes within the lamina propria were observed. Key regulators including the chromatin remodelers ARID4B and SATB1 were found to drive compartment-specific transcriptional programming of CD4 T(reg) cells. ConclusionInflammation in CD patients primarily induces changes within the epithelium and not the lamina propria. Additionally, there is compartment-specific CD4 T cell imprinting, driven by shared regulators, upon translocation from the lamina propria to the epithelium. The main consequence of epithelial translocation, irrespective of inflammation, seems to be an overall dampening of broad (pro-inflammatory) responses and tight regulation of lifespan. These data suggest differential regulation of the lamina propria and epithelium, with a specific regulatory role in the inflamed epithelium.

immunology↗

bioRxiv2022

Human regulatory T-cells locally differentiate and are functionally heterogeneous within the inflamed arthritic joint

ObjectiveTregs are crucial for immune regulation, and environment-driven adaptation of effector (e)Tregs is essential for local functioning. However, the extent of human Treg heterogeneity in inflammatory settings is unclear. MethodsWe combined single-cell RNA- and TCR-sequencing on Tregs derived from 4-6 patients with juvenile idiopathic arthritis (JIA) to investigate the functional heterogeneity of human synovial fluid (SF)-derived Tregs from inflamed joints. Confirmation and suppressive function of the identified Treg clusters was assessed by flow cytometry. ResultsFour Treg clusters were identified; incoming, activated eTregs with either a dominant suppressive or cytotoxic profile, and GPR56+CD161+CXCL13+ Tregs. Pseudotime analysis showed differentiation towards either classical eTreg profiles or GPR56+CD161+CXCL13+ Tregs supported by TCR data. Despite its most differentiated phenotype GPR56+CD161+CXCL13+ Tregs were shown to be suppressive. Furthermore, BATF was identified as an overarching eTreg regulator, with the novel Treg-associated regulon BHLHE40 driving differentiation towards GPR56+CD161+CXCL13+ Tregs, and JAZF1 towards classical eTregs. ConclusionOur study reveals a heterogeneous population of Tregs at the site of inflammation in JIA. SF Treg differentiate to a classical eTreg profile with a more dominant suppressive or cytotoxic profile that share a similar TCR repertoire, or towards GPR56+CD161+CXCL13+ Tregs with a more distinct TCR repertoire. Genes characterizing GPR56+CD161+CXCL13+ Tregs were also mirrored in other T-cell subsets in both the tumor and autoimmune setting. Finally, the identified key regulators driving SF Treg adaptation may be interesting targets for autoimmunity or tumor interventions.

immunology↗