The expression of a transgene encoding the I-E alpha chain prevents a lupus-like autoimmune syndrome in BXSB mice. However, it had not been elucidated whether the E alpha d transgene-mediated protective effect results from I-E expression or from the generation of I-E alpha chain-derived peptides (E alpha peptide) displaying high affinity for the I-Ab molecule. To address this question, two different BXSB lines expressing the transgene at low or high levels were crossed with lupus-prone MRL mice; this resulted in three types of (MRL x BXSB)F1 mice, differing in the expression levels of I-E molecules and of E alpha peptides presented by I-Ab molecules. Comparative analysis of these three (MRL x BXSB)F1 mice as well as several BXSB transgenic lines showed that the E alpha d transgene-mediated protection paralleled the expression levels of E alpha peptide presented by I-Ab molecules, but not of I-E molecules on B cells. In addition, use of transgenic and nontransgenic double bone marrow chimeras showed a selective activation of nontransgenic B cells during I-Ab-restricted T cell-dependent immune responses, while both transgenic and nontransgenic B cells were comparably activated during T cell-independent responses. These results favor a model of autoimmunity prevention based on competition for antigen presentation, in which excessive generation of E alpha peptides prevents, because of their high affinity to the I-A molecules, activation of potential autoreactive T and B cells.