Sex-Defined T-Cell Responses to Cardiac Self Determine Differential Outcomes of Murine Dilated Cardiomyopathy

Daniel Jane-wit^*, Cengiz Z. Altuntas^*, Jennifer Monti, Justin M. Johnson^*, Thomas G. Forsthuber and Vincent K. Tuohy^*

From the Department of Immunology,^*Lerner Research Institute, Cleveland Clinic, Cleveland; and the Department of Pathologyand the Cleveland Clinic Lerner College of Medicine,Case Western Reserve University, Cleveland, Ohio

Idiopathic dilated cardiomyopathy (DCM) is a disease of putativeautoimmune origin that kills males at a twofold to threefoldgreater frequency than females. The reasons underlying thesedifferential outcomes may be related to sex-divergent self-recognition.Here we examined sex-specific autoimmune responses to cardiacself and their impact on DCM development. We found that malesimmunized to the p406-425 peptide derived from mouse cardiac ${alpha}$ -myosin heavy chain preferentially develop a predominant Th17lineage response that provides sustained T-cell memory and ahigh DCM incidence whereas females preferentially develop apredominant Th1 lineage response that becomes anergized to cardiacself resulting in compensatory protection against DCM. The distinctsex-defined disease phenotypes are interchangeable after invivo manipulation of Th1 (interleukin-2) and Th17 (interleukin-17)cytokines. Our study shows that male and female SWXJ mice differentiallyrespond to cardiac self in ways that lead to distinct autoimmuneoutcomes and implies that optimized therapy for autoimmunitymay require consideration of the qualitatively different waysthat males and females engage self.