Antigen-driven CD8+ T cell activation drives the immunopathogenesis of myasthenia gravis–associated myocarditis
Hongxi Chen, Nana Zhang, Ziyan Shi, Ying Zhang, Qin Du, Rui Wang, Xiaofei Wang, Hongyu ZhouAbstract
Purpose
Myasthenia gravis–associated myocarditis (MG-myocarditis) is a life-threatening condition. However, the immune dysregulation underlying its pathogenesis remains poorly defined. This study aimed to delineate the immunological pathways driving myocarditis development in patients with MG.
Methods
We performed integrated single-cell RNA sequencing and paired T cell receptor (TCR) repertoire profiling on peripheral blood mononuclear cells (PBMCs) from 3 patients with MG-myocarditis and 4 patients with MG-only. Analyses were conducted to characterize transcriptional states, differentiation trajectories, clonal expansions, and antigen-specific signatures associated with MG-myocarditis.
Results
Although the overall proportions of major PBMC lineages did not differ significantly between groups, transcriptomic profiling revealed substantial numbers of significantly differentially expressed genes across multiple immune cell subsets. Classical CD14+ monocytes displayed a marked skewing toward a pro-inflammatory differentiation trajectory, accompanied by downregulation of the Activator Protein-1-high intermediate state associated with anti-inflammatory programming. Within the T cell compartment, MG-myocarditis was characterized by robust expansion of TCR clonotypes concurrently enriched in CD8+ effector memory with high EOMES expression and CD8+ effector subsets, indicative of recent or ongoing antigen-driven activation.TCR–peptide binding prediction analysis showed preferential reactivity of these expanded clonotypes toward cardiac proteins—including Titin, MYO10, and MYH6—implicating antigen-specific cytotoxicity in myocardial injury. In parallel, non-classical CD16+ monocytes and conventional dendritic cells (cDCs) exhibited enhanced antigen-presenting signatures, marked respectively by S100A8 upregulation and LY6E downregulation.
Conclusion
Our findings identify non-classical CD16+ monocytes and cDCs as potential cardiac antigen–presenting populations capable of priming pathogenic CD8+ T cell responses, thereby contributing to the immunopathogenesis of MG-associated myocarditis.