Biology subjects

Hodgkin, P. D.

Publications and source records attributed to Hodgkin, P. D..

5 recordsLinked to original sources

bioRxiv2025

Functional immune profiling reveals CD4+ T cell dysregulation associated with celiac disease

T cells integrate signals from antigen and co-stimulatory receptors to calibrate the strength and quality of their responses. This signal integration is influenced by genetic background, which can modulate thresholds for immune tolerance and strength of responses to threat. Celiac disease (CeD) is an autoimmune disorder driven by well-defined genetic risk and characterised by immune dysregulation in response to dietary gluten. However, whether sensitivity or response differences in naive T cell programming contributes to disease susceptibility is not known. To investigate such variation, we developed a sensitive quantitative platform, the momentum assay, which combines standardised, T cell activation with subsequent stimulus withdrawal, enabling measurement of T cell proliferation and survival over time. This assay is integrated with the Cyton2 mathematical model to infer underlying cellular timer programs from population-level dynamics. We applied this method to assess whether naive T cells from individuals with celiac disease (CeD) exhibited altered responses compared to healthy donors (HDs). We found that CD4+ but not CD8+ T cells from CeD patients showed a hypo-proliferative response following stimulation, associated with impaired secretion of the proliferative and pro-survival cytokine IL-2. Moreover, surface expression of early activation marker, CD69 remained elevated for longer on CD4+ T cells from CeD donors after stimulus withdrawal, suggesting prolonged activation and subtle alterations in regulatory feedback mechanisms. These findings reveal previously unrecognised quantitative alterations in naive T cell programming in CeD and underscore the utility of model-based analytical frameworks for detecting subtle functional perturbations in complex immune-mediated diseases.

immunology↗

bioRxiv2023

Molecular control of the lymphocyte death timer

When stimulated, individual lymphocytes program times for division and death that are inherited within families, revealing a common timing mechanism transmitted over generations. Here we describe a threshold-based mechanism for the time to die. By comparing protein levels in control and apoptosis disabled cells, we show that death can be predicted by a cooperating ensemble of BCL-2 family proteins falling below a critical threshold. Single cell measurements predict the time of death with a simple formula, where an additional inhibition factor explains accelerated death induced by BH3 mimetic compounds. Thus, we identify the death timer as a protein-threshold device that underlies signal integration machinery. Together these results reveal that predicting lymphocyte behavior at single cell level, in complex environments, is possible with modular multiscale models that incorporate timers and heritability features of critical proteins.

immunology↗

bioRxiv2020

The clonal and molecular aetiology of emergency dendritic cell development

Extrinsic regulation of single haematopoietic stem and progenitor cell (HSPC) fate is crucial for immune cell development. Here, we examine the aetiology of Flt3 ligand (Flt3L)-mediated emergency development of type 1 conventional dendritic cells (cDC1s), which results in enhanced immunity against infections and cancer. Using cellular barcoding, we demonstrate a predominant role of enhanced clonal expansion and moderate contribution via recruitment of additional cDC1-generating HSPCs. The selective cDC1 expansion occurs primarily via multi-/oligo-potent clones, without compromising output to other lineages. To understand the molecular hallmarks early during a Flt3L response, we develop Divi-Seq to simultaneously profile cell division history, surface phenotype and transcriptional state of single HSPCs. We discover that Flt3L-responsive HSPCs maintain a proliferative early progenitor-like state, which leads to selective emergence of CD11c+cKit+ transitional precursors with high cellular output to cDC1s. These findings inform the mechanistic action of Flt3L in natural immunity and immunotherapy at a clonal level.

immunology↗

bioRxiv2019

Genome reorganization prior to mitosis shapes the generation of adaptive immunity

During cellular differentiation chromosome conformation is altered to support the lineage-specific transcriptional programs required for cell identity. When these changes occur in relation to cell cycle, division and time is unclear. Here we followed B lymphocytes as they differentiated from a naive, quiescent state into antibody secreting plasma cells. Unexpectedly, we found that gene-regulatory chromosome reorganization occurred prior to the first division, in late G1 phase and that this configuration is maintained as the cells rapidly cycle during clonal expansion. A second wave of architectural changes also occurred later as cells differentiated into plasma cells and this was associated with increased time in G1 phase. These data provide an explanation for how lymphocyte fate is imprinted prior to the first division and suggest that chromosome reconfiguration is spatiotemporally separated from DNA replication and mitosis to ensure the implementation of a gene regulatory program that controls the differentiation process required for the generation of immunity.\n\nOne Sentence SummaryDiscrete waves of genome reorganization, spatiotemporally separated from DNA replication and mitosis, control cell differentiation.

genomics↗

bioRxiv2017

Assessment of clonal kinetics reveals multiple trajectories of dendritic cell development

A thorough understanding of cellular development is incumbent on assessing the complexities of fate and kinetics of individual clones within a population. Here, we develop a system for robust periodical assessment of lineage outputs of thousands of transient clones and establishment of bona fide cellular trajectories. We appraise the development of dendritic cells (DCs) from barcode-labeled hematopoietic stem and progenitor cells (HSPCs) by serially measuring barcode signatures, and visualize this multidimensional data using novel developmental interpolated t-distributed stochastic neighborhood embedding (Di-SNE) time-lapse movies. We identify multiple cellular trajectories of DC development that are characterized by distinct fate bias and expansion kinetics, and determine that these are intrinsically programmed. We demonstrate that conventional DC and plasmacytoid DC trajectories are largely separated already at the HSPC stage. This framework allows systematic evaluation of clonal dynamics and can be applied to other steady-state or perturbed developmental systems.

systems biology↗