| First Author | Axelrod ML | Year | 2022 |
| Journal | Nature | Volume | 611 |
| Issue | 7937 | Pages | 818-826 |
| PubMed ID | 36385524 | Mgi Jnum | J:340477 |
| Mgi Id | MGI:7525465 | Doi | 10.1038/s41586-022-05432-3 |
| Citation | Axelrod ML, et al. (2022) T cells specific for alpha-myosin drive immunotherapy-related myocarditis. Nature 611(7937):818-826 |
| abstractText | Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy(1). The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1(-/-)Ctla4(+/-) mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration(2). Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1(-/-)Ctla4(+/-) mice, we identify clonal effector CD8(+) T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1(-/-)Ctla4(+/-) mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, which required CD8(+) T cells. The cardiac-specific protein alpha-myosin, which is absent from the thymus(3,4), 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 alpha-myosin peptides. Moreover, these alpha-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that alpha-myosin may be a clinically important autoantigen in ICI-MC. These studies underscore the crucial role for cytotoxic CD8(+) T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity. |
