In humans, spontaneous autoimmune attack against cardiomyocytes often leads to idiopathic dilated cardiomyopathy (IDCM) and life-threatening heart failure. HLA-DQ8 transgenic IAb knockout NOD mice (NOD. DQ8/Ab 0; DQA1* 0301, DQB1* 0302) develop spontaneous anticardiomyocyte autoimmunity with pathology very similar to human IDCM, but why the heart is targeted is unknown. In the present study, we first investigated whether NOD/Ab 0 mice transgenic for a different DQ allele, DQ6,(DQA1* 0102, DQB1* 0602) would also develop myocarditis. NOD. DQ6/Ab 0 animals showed no cardiac pathology, implying that DQ8 is specifically required for the myocarditis phenotype. To further characterize the cellular immune mechanisms, we established crosses of our NOD. DQ8/Ab 0 animals with Rag1 knockout (Rag1 0), Ig H chain knockout (IgH 0), and β 2-microglobulin knockout (β 2 m 0) lines. Adoptive transfer of purified CD4 T cells from NOD. DQ8/Ab 0 mice with complete heart block (an indication of advanced myocarditis) into younger NOD. DQ8/Ab 0 Rag1 0 animals induced cardiac pathology in all recipients, whereas adoptive transfer of purified CD8 T cells or B lymphocytes had no effect. Despite the absence of B lymphocytes, NOD. DQ8/Ab 0 IgH 0 animals still developed complete heart block, whereas NOD. DQ8/Ab 0 β 2 m 0 mice (which lack CD8 T cells) failed to develop any cardiac pathology. CD8 T cells (and possibly NK cells) seem to be necessary to initiate disease, whereas once initiated, CD4 T cells alone can orchestrate the cardiac pathology, likely through their capacity to recruit and activate macrophages. Understanding the cellular immune mechanisms causing spontaneous myocarditis/IDCM in this relevant animal model will facilitate the development and testing of new therapies for this devastating disease.