Costimulatory molecules, termed B7.1 and B7.2, are present on the surfaces of APC and are important for the activation of T lymphocytes specific for both foreign Ags and autoantigens. We have examined the role of B7 costimulation in the MRL-lpr/lpr murine model of human systemic lupus erythematosus. MRL-lpr/lpr mice receiving both anti-B7.1 and anti-B7.2 Abs expressed significantly lower anti-small nuclear ribonucleoprotein particles (snRNP) and anti-dsDNA autoantibodies than did untreated mice. Anti-B7.2 Ab treatment alone inhibited anti-dsDNA autoantibody expression while having no effect on anti-snRNP autoantibody expression. Anti-B7.1 Ab treatment alone did not change the expression of either anti-snRNP or anti-dsDNA autoantibodies. Parallel studies performed in MRL-lpr/lpr mice genetically deficient in either B7.1 or B7.2 expressed autoantibody profiles comparable to those found in wild-type MRL-lpr/lpr mice. However, B7.1-deficient MRL-lpr/lpr mice exhibited distinct and more severe glomerulonephritis while B7.2-deficient MRL-lpr/lpr mice had significantly milder or absent kidney pathology as compared with age-matched wild-type mice. These studies indicate that each B7 costimulatory signal may control unique pathological events in murine systemic lupus erythematosus that may not always be apparent in autoantibody titers alone.