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Axelrod, Margaret L; Meijers, Wouter C; Screever, Elles M; Qin, Juan; Carroll, Mary Grace; Sun, Xiaopeng; Tannous, Elie; Zhang, Yueli; Sugiura, Ayaka; Taylor, Brandie C; Hanna, Ann; Zhang, Shaoyi; Amancherla, Kaushik; Tai, Warren; Wright, Jordan J; Wei, Spencer C; Opalenik, Susan R; Toren, Abigail L; Rathmell, Jeffrey C; Ferrell, P Brent; Phillips, Elizabeth J; Mallal, Simon; Johnson, Douglas B; Allison, James P; Moslehi, Javid J; Balko, Justin M
Nature, 11/2022, Letnik: 611, Številka: 7937Journal Article
Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy . 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 . 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 α-myosin, which is absent from the thymus , 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 T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity.
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Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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