T cells specific for α-myosin drive immunotherapy-related myocarditis
Open accessPublished version of a preprint
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 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 α-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 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. Cytotoxic CD8 + T cells specific for α-myosin are identified as pivotal players in myocarditis associated with immune checkpoint inhibitor anticancer therapies.
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Autoreactive T cells that recognize α-MyHC naturally develop in every individual.
“autoreactive T cells that recognize α -MyHC naturally develop in every individual”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [41]
The section “α-myosin TCRs are found in ICI-MC patients” reports expandable α-myosin-specific T cells in the healthy donors and patients tested. The Discussion says their presence is likely common in humans, but neither passage establishes that these cells naturally develop in every individual. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe gene for α-MyHC is not expressed in medullary thymic epithelial cells, which are crucial for negative selection during T-cell development.
“the gene for α -MyHC is not expressed in medullary thymic epithelial cells, which are crucial for negative selection during T-cell development.”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [41]
In “Myocarditis TCRs recognize α-myosin” (page unavailable), the paper reports no detectable thymic expression of MYH6, the gene encoding α-myosin, and links that absence to escape from negative selection. It describes data on thymic antigen-presenting cells and thymus tissue, but does not specifically establish non-expression in medullary thymic epithelial cells or identify those cells as crucial to negative selection. (LLM, conf=0.82)
Experimental — accuracy not yet measuredFollowing ICI therapy, 40% of patients with myocarditis experience concomitant myositis, confirmed in mouse models.
“Following ICI therapy, 40% of patients with myocarditis experience concomitant myositis, confirmed in mouse models. 41,42,46,68,282”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [41]
The Abstract (page unavailable) says ICI-related myocarditis often co-occurs with myositis, but gives no 40% figure. It also says severe inflammation in the mouse model is specific to the heart, so the model does not confirm concomitant myositis. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAutoreactive T cells targeting α-MyHC may play a pivotal role in the development and progression of ICI myocarditis.
“Recent animal studies have suggested that autoreactive T cells targeting α -MyHC, rather than tumor antigens, may play a pivotal role in the development and progression of ICI myocarditis”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [41]
The Abstract and Discussion report that α-myosin-specific CD8+ T cells contribute to myocarditis in the mouse model and suggest α-myosin may be an important autoantigen in patients. The paper does not establish the citing sentence’s contrast with tumor antigens; the Discussion also notes that other antigens may be relevant. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAbatacept and ruxolitinib are effective in attenuating myocarditis in preclinical models.
“abatacept (a T-cell costimulation inhibitor) and ruxolitinib (an inhibitor for Janus kinase signaling critical in macrophage-T-cell crosstalk) have been shown to be effective in attenuating myocarditis in preclinical models.”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [41]
The paper’s Abstract (page unavailable) reports that abatacept attenuated myocarditis and increased survival in a mouse model. Our copy does not report a preclinical myocarditis result for ruxolitinib, so it supports only the abatacept part of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Macrophage-T-cell interaction is critical for the propagation of ICI myocarditis.
“with macrophage-T-cell interaction critical for its propagation.”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [41]
The Abstract and “CD8+ T cells are necessary for myocarditis” section (page not provided) show that CD8+ T cells are necessary for myocarditis in the mouse model. The Abstract also notes macrophages in affected hearts, but the cited passages do not establish that macrophage–T-cell interaction is critical for disease propagation. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe discovery of α-MyHC-specific T cells in ICI myocarditis suggests potential involvement of autoreactive T cells targeting α-MyHC in the initiation and progression of other forms of myocarditis.
“This discovery suggests a potential involvement of autoreactive T cells targeting α -MyHC in the initiation and progression of other forms of myocarditis.”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [41]
The Discussion (page unavailable) suggests that α-myosin may be an important autoantigen in ICI-related myocarditis, and the patient-results section reports α-myosin-specific T cells in affected hearts. The paper does not extend that suggestion to the initiation or progression of other forms of myocarditis. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn preclinical models of ICI myocarditis, T cells are necessary for the development of myocarditis.
“Data from preclinical models of ICI myocarditis suggested that T cells are necessary for the development of myocarditis”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [41]
The HLA-A*03:01 allele can present α-MyHC peptide to T cells.
“Another study revealed that the HLA-A*03:01 allele can present α -MyHC peptide to T cells. 41”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [41]
In this model, clonal and activated CD8+ T lymphocytes are necessary for the development of myocarditis, and autoreactive α-MyHC-specific T cells are a crucial mediator of disease pathogenesis.
“clonal and activated CD8 + T lymphocytes are necessary for the development of myocarditis, with further investigation identifying autoreactive α -MyHC-specific T cells as a crucial mediator of disease pathogenesis”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [41]
Clonal expansion of α-MyHC-specific T cells was observed in PBMCs and myocardium of patients with ICI myocarditis, suggesting a role for these T cells in human pathogenesis.
“clonal expansion of α -MyHC-specific T cells was observed in the PBMCs and myocardium of patients with ICI myocarditis, suggesting (though not proving) a role for these T cells in the pathogenesis of myocarditis in humans”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [41]
Clonal expansion of autoreactive T cells targeting α-MyHC is observed in patients with ICI myocarditis.
“Similarly, clonal expansion of these autoreactive T cells was observed in patients with ICI myocarditis.”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [41]
PBMC T cells isolated from healthy donors exhibit expansion when in vitro cultured with α-MyHC.
“PBMC T cells isolated from healthy donors exhibited expansion when in vitro cultured with α -MyHC”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [41]
T cells from patients with myocarditis exhibit expansion when in vitro cultured with α-MyHC.
“and T cells from patients with myocarditis.”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [41]
Recent cases of ICI myocarditis have expanded insights into the role of α-MyHC-specific T cells in myocarditis development.
“Recent cases of ICI myocarditis have expanded our insights into the role of α -MyHC-specific T cells in myocarditis development. 41-46”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [41]
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Lee, J.-H., Kim, T.-H., Park, H. E., Lee, E. G., Jung, N.-C., Song, J.-Y., Seo, H. G., Seung, K.-B., Chang, K., & Lim, D.-S. (2014) · Cardiovascular Research · doi:10.1093/cvr/cvt246 · Cited by 50 · see citing works
HLA Expression Correlates to the Risk of Immune Checkpoint Inhibitor-Induced Pneumonitis
Correale, P., Saladino, R. E., Giannarelli, D., Sergi, A., Mazzei, M. A., Bianco, G., Giannicola, R., Iuliano, E., Forte, I. M., Calandruccio, N. D., et al. (2020) · Cells · doi:10.3390/cells9091964 · Cited by 50 · see citing works
Yang, X., Bam, M., Becker, W., Nagarkatti, P. S., & Nagarkatti, M. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.2000330 · Cited by 49 · see citing works
der Borght, K. V., Scott, C. L., Martens, L., Sichien, D., Isterdael, G. V., Nindl, V., Saeys, Y., Boon, L., Ludewig, B., Gillebert, T. C., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02714 · Cited by 44 · see citing works
immunomind/immunarch: 0.6.5: Basic single-cell support
Nazarov, V. I., Immunarch.Bot, & Rumynskiy, E. (2020) · Zenodo (CERN European Organization for Nuclear Research) · doi:10.5281/zenodo.3893991 · Cited by 26 · see citing works
Transcriptomes of antigen presenting cells in human thymus
Gabrielsen, I. S. M., Helgeland, H., Akselsen, H., D. Aass, H. C., Sundaram, A. Y. M., Snowhite, I. V., Pugliese, A., Flåm, S. T., & Lie, B. A. (2019) · PLOS ONE · doi:10.1371/journal.pone.0218858 · Cited by 21 · see citing works
Tajiri, K., Imanaka‐Yoshida, K., Tsujimura, Y., Matsuo, K., Hiroe, M., Aonuma, K., Ieda, M., & Yasutomi, Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020794 · Cited by 9 · see citing works
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Diagnosis and Treatment of Acute Myocarditis: A Review
Ammirati, E., & Moslehi, J. J. (2023) · JAMA · doi:10.1001/jama.2023.3371 · Cited by 379 · see citing works
Self-citationExpansion of Pathogenic Cardiac Macrophages in Immune Checkpoint Inhibitor Myocarditis
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Self-citationGougis, P., Jochum, F., Abbar, B., Dumas, E., Bihan, K., Lebrun-Vignes, B., Moslehi, J., Spano, J.-P., Laas, E., Hotton, J., et al. (2024) · eClinicalMedicine · doi:10.1016/j.eclinm.2024.102536 · Cited by 161 · see citing works
Self-citationImmune checkpoint inhibitors associated cardiovascular immune-related adverse events
Jo, W., Won, T., Daoud, A., & Čiháková, D. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1340373 · Cited by 55 · see citing works
Autoimmune Myocarditis, Old Dogs and New Tricks.
Won, T., Song, E. J., Kalinoski, H. M., Moslehi, J. J., & Čiháková, D. (2024) · Circulation Research · doi:10.1161/circresaha.124.323816 · Cited by 51 · see citing works
Self-citationSpatiotemporal transcriptomics elucidates the pathogenesis of fulminant viral myocarditis
Li, H., Chen, X., Wang, J. J., Shen, J., Abuduwufuer, K., Zhang, Z., Dong, Z., Wen, Z., He, J., Chen, S., et al. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02143-9 · Cited by 40 · see citing works
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- Authors
- Axelrod, M. L., Meijers, W. C., Screever, E. M., Qin, J., Carroll, M. G., Sun, X., Tannous, E., Zhang, Y., Sugiura, A., Taylor, B. C., Hanna, A., Zhang, S., Amancherla, K., Tai, W., Wright, J. J., Wei, S. C., Opalenik, S. R., Toren, A. L., Rathmell, J. C., Ferrell, P. B., Phillips, E. J., Mallal, S., Johnson, D. B., Allison, J. P., Moslehi, J. J., & Balko, J. M.
- Affiliations
- Vanderbilt University Medical Center (US)
- University Medical Center Groningen (NL)
- University of California, San Francisco (US)
- University of California, Los Angeles (US)
- The University of Texas MD Anderson Cancer Center (US)
- Vanderbilt-Ingram Cancer Center (US)
- Murdoch University (AU)
- Corresponding author
- Moslehi, Javid J.
- Balko, Justin M.
- ORCID
- Axelrod, Margaret L.
- Meijers, Wouter C.
- Screever, Elles M.
- Qin, Juan
- 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.
- Rathmell, Jeffrey C.
- Ferrell, P. Brent
- Phillips, Elizabeth J.
- Mallal, Simon
- Johnson, Douglas B.
- Allison, James P.
- Moslehi, Javid J.
- Balko, Justin M.
- Venue
- Nature
- Published
- 2022-11-16
- Volume
- 611
- Issue
- 7937
- Pages
- 818-826
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9930174
- OpenAlex
- W4309413232
- Semantic Scholar
- 7f0e636729719723ab37151355c607bc4827bec6
- Cited by
- 367
- References
- 65
- Citations by year
- 2026: 102 · 2025: 84 · 2024: 90 · 2023: 83 · 2022: 7
- FWCI
- 27.62
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- American Heart Association
- Vanderbilt University Medical Center
- National Institutes of Health (1s10od023475-01a1, 1s10od025092-01a1, UL1TR002243)
- National Heart, Lung, and Blood Institute (K23HL138291, T32HL007895, R01HL141466, R01HL156021, R01HL155990)
- National Human Genome Research Institute (R01HG010863)
- National Eye Institute (P30EY008126)
- National Cancer Institute (F30CA236157, R01CA227481, P30CA016672, P30CA068485, R01CA217987)
- National Institute of General Medical Sciences (T32GM007347)
- National Institute of Allergy and Infectious Diseases (P30AI110527, R01AI152183, U01AI154659)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007061)
- National Center for Research Resources (UL1RR024975, G20RR030956)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- immune checkpoint inhibitor-associated myocarditis, CD8+ T cells, autoantigens, T cell clonotypes, immune-related adverse events, adoptive transfer, cancer immunotherapy toxicity
- MeSH terms
- Animals, Autoantigens, Immunotherapy, Myocarditis, CD8-Positive T-Lymphocytes, Ventricular Myosins, Mice, CTLA-4 Antigen, Programmed Cell Death 1 Receptor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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