Non-tolerant B cells cause autoimmunity in anti-CD8 IgG2a-transgenic mice

Using a pair of gamma 2a/chi immunoglobulin genes, transgenic mice were generated to study tolerance induction in B cells that express IgG2a autoantibodies. The transgenic IgG2a specifically binds CD8 alpha chains of the CD8.2 allotype expressed on the surface of CD8+ T cells, but not CD8 molecules expressed by the CD8.1 allele. Thus, IgG2a transgenic mice expressing the CD8.1 allele were used as controls to monitor B cell development and mice expressing CD8.2 were used to study B cell tolerance. Both types of mice showed transgenic gamma 2a expression on the surface of B cells. Expression of endogenous heavy chain alleles was strongly inhibited in immature B cell subsets, whereas mature B cells co-expressed transgenic gamma 2a and endogenous IgM/D. The transgenic chi chain expression leads only to partial allelic exclusion of endogenous light chains. B cells that express high levels of transgenic CD8.2-specific IgG2a were identified using soluble CD8-Ig. In CD8.1+ and in CD8.2+ mice, we found no differences in expression and maturation of transgenic anti-CD8.2 IgG2a+ B cells. High levels of serum anti-CD8.2 IgG2a antibodies led to the elimination of CD8+ T cells, causing a severe defect in cytotoxic immune responses. These results show that tolerance induction is incomplete in the CD8.2+ mice, either because IgG2a+ B cells are resistant to censoring mechanisms or because the secreted CD8-specific IgG2a antibodies render the CD8 autoantigen inaccessible to the B cells. This contrasts strongly with the efficient induction of B cell tolerance in mice expressing anti-CD8.2 IgM autoantibodies.