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

Kyaw, T. S.; Kanellakis, P.; Le, A.; Lye, Y. E.; Patel, P.; Brassington, K.; Dayawanmsa, N.; Figueiredo Galvao, H. B.; Drummond, G. R. B.; Sobey, C. G.; Bobik, A.; Peter, K.

doi:10.64898/2026.05.01.722122

bioRxiv · 10.64898/2026.05.01.722122

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

Kyaw, T. S.·Kanellakis, P.·Le, A.·Lye, Y. E.·Patel, P.·Brassington, K.·Dayawanmsa, N.·Figueiredo Galvao, H. B.·Drummond, G. R. B.·Sobey, C. G.·Bobik, A.·Peter, K.

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Abstract

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.

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Kyaw, T. S., Kanellakis, P., Le, A., Lye, Y. E., Patel, P., Brassington, K., Dayawanmsa, N., Figueiredo Galvao, H. B., Drummond, G. R. B., Sobey, C. G., Bobik, A., Peter, K.. 2026-05-05. Immune-Mediated Necrotic Cell Death Initiated by Stressed Cardiomyocytes is a Major Contributor to Cardiomyocyte Loss Following Myocardial Infarction. https://doi.org/10.64898/2026.05.01.722122

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