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T cells specific for α-myosin drive immunotherapy-related myocarditis.
- Source :
-
Nature [Nature] 2022 Nov; Vol. 611 (7937), pp. 818-826. Date of Electronic Publication: 2022 Nov 16. - Publication Year :
- 2022
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Abstract
- Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy <superscript>1</superscript> . The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1 <superscript>-/-</superscript> Ctla4 <superscript>+/-</superscript> mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration <superscript>2</superscript> . Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1 <superscript>-/-</superscript> Ctla4 <superscript>+/-</superscript> mice, we identify clonal effector CD8 <superscript>+</superscript> T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1 <superscript>-/-</superscript> Ctla4 <superscript>+/-</superscript> mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, which required CD8 <superscript>+</superscript> T cells. The cardiac-specific protein α-myosin, which is absent from the thymus <superscript>3,4</superscript> , was identified as the cognate antigen source for three major histocompatibility complex class I-restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-MC were expanded by α-myosin peptides. Moreover, these α-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that α-myosin may be a clinically important autoantigen in ICI-MC. These studies underscore the crucial role for cytotoxic CD8 <superscript>+</superscript> T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity.<br /> (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 611
- Issue :
- 7937
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 36385524
- Full Text :
- https://doi.org/10.1038/s41586-022-05432-3