Abstract Body (Do not enter title and authors here): Cardiac inflammation is increasingly recognized as an important aspect of arrhythmogenic right ventricular cardiomyopathy (ARVC), a genetic cardiac disease characterized by loss of cardiomyocytes and their gradual replacement by fibro-fatty tissue, resulting in cardiac dysfunction and sudden cardiac death. Mutations in desmosomal genes, which serve as essential mechanical anchors between cardiac muscle cells, are a principal cause of ARVC. Patients with mutations in the desmosomal gene, desmoplakin (DSP) exhibit a distinct cardiomyopathy, marked by its strong association with myocarditis and recurrent inflammatory episodes, leading to aggravated cardiac outcomes. However, the precise role of inflammation in driving of DSP-mediated cardiomyopathy remains to be fully elucidated. We hypothesize that DSP deficiency alters the cardiomyocyte response to acute inflammatory response, leading to chronic immune intolerance and ultimately triggering ARVC disease progression. To test our hypothesis, we subjected cardiac-specific DSP heterozygous (DSP Het) deficient mice, which displayed 50% loss in DSP protein levels and remained asymptomatic for a year, to an acute immunological challenge. This allowed us to evaluate the chronic impact on ARVC pathogenesis in the absence of pre-existing cardiac disease. Our findings reveal that acute immunological challenge in DSP Het mice elicits a destructive cardiomyocyte immune response, akin to fulminant myocarditis. Furthermore, this acute challenge is sufficient to induce classic ARVC features in DSP Het deficient mice as exemplified by: (i) enlarged heart size and ventricular chambers, (ii) fibrotic remodeling, (iii) epicardial fat tissue accumulation, with pronounced effects on the right ventricle. Additionally, we observed electrophysiological deficits, such as premature ventricular contractions and QRS prolongation, along with functional deficits associated with bi-ventricular form of ARVC, albeit with a greater impact on the right ventricle. Single nuclei RNA sequencing studies in mice revealed the presence and differences in T cell populations in hearts from mice with DSP-related myocarditis, indicating early immune antigen recognition as a potential mechanism driving disease. These studies suggest that the immune system may be an important driver of ARVC pathogenesis in patients with underlying desmosomal gene mutations, such as DSP, especially in the setting of autosomal dominant genetics.