Biology subjects

Bongcaron, V.

Publications and source records attributed to Bongcaron, V..

3 recordsLinked to original sources

bioRxiv2026

Autoimmune-like CD8⁺ T Cell Responses Drive Atherosclerotic Plaque Instability and Predict Cardiovascular Events

Background and aimsAtherosclerotic plaque rupture is a major cause of myocardial infarction and stroke. However, the precise drivers of plaque destabilisation remain elusive. We hypothesised that antigen-driven, autoimmune-like T cell responses are central to the destabilisation and rupture of atherosclerotic plaques. MethodsTo dissect T cell responses specifically in unstable compared to stable plaques, we leveraged near-infrared autofluorescence (NIRAF) imaging-guided dissection of human carotid plaques. We also used our tandem stenosis model reflecting plaque instability as seen in patients to differentiate between unstable and stable plaques in mice. To explore T cell involvement, we studied T cell differentiation states and T cell receptor (TCR) repertoires by single-cell multi-omics. Then, testing if antigen-driven CD8+ T cell responses drive plaque instability in mice, we applied a combination of AAV8-PCSK9-induced atherosclerosis, tandem stenosis and TCR transgenic mice. Finally, we leveraged data from the AtheroExpress Biobank Study to link T cell immunity to histology-defined instability and cardiovascular outcomes. ResultsT cell responses in unstable versus stable atherosclerosis were distinct. Unstable human plaques contained highly expanded, autoimmune-like CD8 T cells with markedly increased cytotoxic signatures, reduced exhaustion and distinct clonal repertoires compared to stable regions. Most plaque CD8 T cells exhibited a pronounced tissue-resident transcriptional program. Moreover, the transcriptional signature of these plaque resident T cells was distinct from multiple other human tissues. Autoimmune-like cytotoxic and tissue-resident CD8+ T cell responses were also evident in murine atherosclerosis, where restricting the activation of antigen-driven CD8+ T cells prevented plaque destabilisation. Importantly, analysis of carotid endarterectomy samples from >1000 patients identified that intraplaque cytotoxic CD8 T cell gene signatures strongly correlated with histological instability and predicted future strokes. ConclusionsIntegrated human, murine and clinical analyses demonstrate that autoimmune-like, cytotoxic CD8 T cell responses are central drivers of plaque instability and major cardiovascular events. Targeting pathogenic CD8 T cell responses may thus offer a compelling immunomodulatory strategy to stabilise plaques and reduce the risks of stroke and myocardial infarction. Graphical AbstractO_ST_ABSKey QuestionC_ST_ABSRupture of unstable atherosclerotic plaques is a typical cause of myocardial infarction and stroke. To understand the underlying cause and to prevent plaque rupture, we addressed the central hypothesis that autoimmune-like T cell responses drive plaque destabilisation and rupture. Key FindingsCD8+ T cells are clonally expanded with increased cytotoxic signatures in unstable versus stable plaques (mice and humans) and require antigen recognition to drive plaque instability. Cytotoxic CD8+ T cell signatures in excised plaques correlate with increased future cardiovascular events. Take Home MessageAutoimmune-like adaptive immune reactions, dominated by CD8+ T cells, are a major driver of plaque instability/rupture. Therefore, targeting pathogenic CD8 T cell responses offers a compelling immunomodulatory strategy to stabilise plaques and reduce the risk of myocardial infarction and stroke. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/720043v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@bd83dcorg.highwire.dtl.DTLVardef@1bee3borg.highwire.dtl.DTLVardef@1b56bc0org.highwire.dtl.DTLVardef@1b5176f_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Endothelial-targeted CD39 prevents Toxin-induced Pulmonary Hypertension Mice.

Disruption of the pulmonary endothelium by drugs, toxins, viruses (e.g., COVID-19), or bacterial sepsis can cause acute pulmonary vasculopathy leading to pulmonary hypertension and consequential heart failure. CD39 is a membrane-anchored ecto-enzyme expressed on endothelial cells (EC), integral in maintaining the antithrombotic profile of the endothelium. This ecto-enzyme works in concert with CD73 to hydrolyze both eATP (pro-inflammatory) and ADP (pro-thrombotic) ultimately to adenosine, which is anti-inflammatory, vasodilatory, and antithrombotic. CD39 activity and adenosine signalling are disrupted in idiopathic pulmonary arterial hypertension (PAH). In this work, we explored the efficacy of endothelial cell-targeted delivery of CD39 to prevent the development of acute toxin-induced PAH in a mouse model. We generated a novel therapeutic anti-VCAM-CD39 containing an scFv recognising VCAM-1 (a receptor expressed on activated EC) fused to the soluble form of extracellular human CD39. In a mouse model of endothelial cell-toxin-induced PAH, we show that a single administration of anti-VCAM-CD39 (0.4 mg/kg IV) prevented the development of PAH-- as reflected in the preservation of right ventricular systolic pressures and the absence of right ventricular hypertrophy at day 10 when compared with controls. This protection is conferred by multiple mechanisms: IL-10-driven potentiation of heme oxygenase (HO)-1, a known inhibitor of smooth muscle proliferation; VCAM-1 blockade reduces leukocyte adhesion to the endothelium; and cytoprotective effects through adenosine signalling. Thus, anti-VCAM-CD39 is a novel bifunctional therapeutic strategy for PAH.

physiology↗

bioRxiv2023

Therapeutic immunization with a whole cell vaccine reduces pneumococcal nasopharyngeal density, shedding, and middle ear infection in mice

Pneumococcal Conjugate Vaccines (PCVs) have substantially reduced the burden of disease caused by Streptococcus pneumoniae (the pneumococcus). However, protection is limited to vaccine serotypes, and when administered to children who are colonized with pneumococci at the time of vaccination, immune responses to the vaccine are blunted. Here, we investigate the potential of a killed whole cell pneumococcal vaccine (WCV) to reduce existing pneumococcal carriage and mucosal disease when given therapeutically to infant mice colonized with pneumococci. We show that a single dose of WCV reduced pneumococcal carriage density in an antibody-dependent manner. Therapeutic vaccination induced robust immune responses to pneumococcal surface antigens CbpA, PspA (family 1) and PiaA. In a co-infection model of otitis media, a single dose of WCV reduced pneumococcal middle ear infection. Lastly, in a two-dose model, therapeutic administration of WCV reduced nasal shedding of pneumococci. Taken together, our data demonstrate that WCV administered in colonized mice reduced pneumococcal density in the nasopharynx and the middle ear, and decreased shedding. A vaccine with similar properties in children would be beneficial in low and middle-income settings where pneumococcal carriage is high. ImportanceAlthough typically asymptomatic, pneumococcal carriage plays an essential role in transmission and the development of disease. Pneumococcal Conjugate Vaccines (PCVs) have reduced the burden of pneumococcal disease worldwide. However, their use has increased carriage and disease caused by non-vaccine serotypes, prompting investigations into serotype-independent pneumococcal vaccines. An additional limitation of PCVs is immune hypo-responsiveness to vaccines in children carrying pneumococci at the time of vaccination. Therefore, there is great interest in next generation vaccines such as whole cell vaccines. In this study we investigate a pneumococcal whole cell vaccine (WCV) for it effect on carriage in mice that are already colonized at the time of vaccination. We show that this therapeutic vaccination of mice can reduce pneumococcal carriage density, shedding and infection of the middle ear. Our study suggests that WCV could be beneficial in high burden settings where carriage at the time of vaccination is more common.

microbiology↗