Biology subjects

Kanellakis, P.

Publications and source records attributed to Kanellakis, P..

3 recordsLinked to original sources

bioRxiv2026

Immune-Mediated Necrotic Cell Death Initiated by Stressed Cardiomyocytes is a Major Contributor to Cardiomyocyte Loss Following Myocardial Infarction

AimsPercutaneous coronary intervention has improved survival following myocardial infarction, yet strategies to further reduce infarct size are limited. This study investigates the role of cytotoxic {gamma}{delta}-T cells in ischemic cardiomyocyte death and potential therapeutic interventions to reduce infarct size. MethodsGenetic and pharmacological approaches were used to delete {gamma}{delta}-T cells and their specific proteins to assess their involvement in cardiomyocyte death using mouse models of permanent ligation (PL) and ischemia/reperfusion (IR). Results{gamma}{delta}-T cells accumulated in infarct zones within 6h post-PL, expressing IFN-{gamma}, TNF-, granzyme B, and perforin. Their deletion reduced infarct size by 73% (PL) and 64% (IR). They induced cardiomyocyte death via apoptosis, gasdermin E-dependent pyroptosis, and MLKL-dependent necroptosis; {gamma}{delta}-T cell depletion reduced apoptosis by 80% and pyroptosis by 38%, with perforin deletion yielding similar effects. Necroptosis, attributed to combined IFN-{gamma}/TNF- cytotoxicity, decreased by 67%. Cytoplasmic DNA (cDNA) in stressed cardiomyocytes activated the cGAS/STING pathway, inducing expression of chemoattractant MCP-1 and death signal RAE-1. These signals recruited and activated {gamma}{delta}-T cells, which then triggered the death of the stressed cardiomyocytes. STING inhibition suppressed these expressions, reducing {gamma}{delta}-T cell accumulation and infarct size. NKG2D-deficient {gamma}{delta}-T cells prevented activation and reduced infarct size. Administration of an anti-IFNAR antibody at PL onset markedly reduced infarct size. ConclusionEarly activation of cytotoxic {gamma}{delta}-T cells via cardiomyocyte stress signals contributes significantly to immunogenic cardiomyocyte death. Targeting the STING pathway and type I interferon signalling presents a promising therapeutic avenue to mitigate infarct size and improve outcomes.

immunology↗

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

CD27+ γδ T Cells Drive Plaque Instability in Advanced Atherosclerosis: Targeting CXCR3 for Therapeutic Intervention

BackgroundAtherosclerosis is a chronic inflammatory disease of the arterial wall that underlies most myocardial Ischaemic events. While multiple immune subsets contribute to plaque progression and instability, the role of {gamma}{delta} T cells remains poorly understood. We examined the contribution of {gamma}{delta} T cells to lesion development, progression and instability, and explored the therapeutic potential of their pharmacological blockade. MethodsTo investigate the role of {gamma}{delta} T cells, chimeric atherosclerosis-prone mice lacking {gamma}{delta} T cells were utilized in both loss- and gain-of-function experiments. Mixed bone marrow chimeras were generated to assess the role of {gamma}{delta} T cell-derived interferon-{gamma} (IFN-{gamma}) and perforin (Pfp). The therapeutic efficacy of AMG487 on plaque stability was evaluated in a preclinical tandem-stenosis mouse model. Lesion size, plaque composition, and stability were assessed using histology, immunoassays, and molecular biology techniques. ResultsCD27+ {gamma}{delta} T cells accumulated in atherosclerotic lesions and promoted plaque progression and instability via IFN-{gamma}- and Pfp-dependent manners. As early infiltrators, they amplified necrosis and inflammation by enhancing immune cell recruitment, thereby exacerbating lesion vulnerability. CXCR3 antagonism with AMG487 inhibited {gamma}{delta} T cell recruitment to plaques, reduced lesion size, and promoted features of plaque stability, including increased smooth muscle cell content and thicker fibrous caps. ConclusionsCD27 {gamma}{delta} T cells, which promote inflammation and necrosis through both direct and indirect mechanisms, are key drivers of plaque progression and instability. Targeting their recruitment via CXCR3 blockade enhances plaque stability and may represent a promising therapeutic strategy to reduce the risk of myocardial infarction.

immunology↗