T-cell dependent autoimmunization with nucleosomes appears to be an early event in the induction of lupus anti-chromatin antibodies. We investigated this phenomenon by injecting H1-stripped chromatin polynucleosomes into the thymuses of BXSB male lupus-prone mice. In comparison to uninjected controls, the production of IgG antichromatin, anti-native DNA, and anti-denatured DNA were significantly reduced among the injected animals for a period of 8 to 10 weeks. Peripheral T-cells from intrathymic (i.t.)-treated animals showed decreased proliferative responses to polynucleosomes compared to those from uninjected controls. Treatment did not affect T-cell antigen receptor V beta profiles, excluding the possibility that results were due to superantigen-imposed deletions. In situ staining using the TUNEL method demonstrated that generation and phagocytosis of apoptotic material in thymuses of unmanipulated BXSB mice were similar to normal controls. These findings show that polynucleosomes likely comprise the antigens for helper T-cell engagement and induction of lupus-associated anti-chromatin antibodies. Bypassing the underlying defect of T-cell tolerance for polynucleosomal antigens among BXSB mice, by i.t. administration of exogenous polynucleosomes, results in abrogation of autoantibody production.