MRL-lpr mice develop aggressive autoimmune kidney disease associated with increased or de novo renal expression of major histocompatibility complex (MHC) class II molecules and a massive systemic expansion of CD4-CD- double negative (DN) T cells. Whereas non-MHC linked genes can have a profound effect on the development of nephritis, lymphadenopathy, and anti-DNA antibody production in MRL-lpr mice, the role of MHC molecules has not been unequivocally established. To study the role of MHC class II in this murine model of systemic lupus erythematosis, class II-deficient MRL-lpr mice (MRL-lpr -/-) were created. MRL-lpr -/- mice developed lymphadenopathy but not autoimmune renal disease or autoantibodies. This study demonstrates that class II expression is critical for the development of autoaggressive CD4+ T cells involved in autoimmune nephritis and clearly dissociates DN T cell expansion from autoimmune disease initiation.