The susceptibility locus for the autoimmune disease lupus on murine chromosome 1, Sle1^z/Sle1b^z, and the orthologous human locus are associated with production of autoantibody to chromatin. We report that the presence of Sle1^z/Sle1b^z impairs B cell anergy, receptor revision, and deletion. Members of the SLAM costimulatory molecule family constitute prime candidates for Sle1b^z, among which the Ly108.1 isoform of the Ly108 gene was most highly expressed in immature B cells from lupus-prone B6.Sle1^z mice. The normal Ly108.2 allele, but not the lupus-associated Ly108.1 allele, was found to sensitize immature B cells to deletion and RAG reexpression. As a potential regulator of tolerance checkpoints, Ly108 may censor self-reactive B cells, hence safeguarding against autoimmunity.