THE recessive mouse mutations lpr and gld create deficiencies in an interacting pair of cell surface molecules, CD95 (Fas/APO-1) and Fas-ligand (FasL), respectively^1–3, resulting in autoantibody production resembling human systemic lupus erythematosus⁴. The mechanisms of self-tolerance affected by deficiency in either molecule are not established, but CD95 deficiency both in B cells and in CD4⁺ T cells recognizing major histocompatibility complex (MHC) class II molecules is required for autoimmunity in lpr mice^5–8. Here we track the outcome of in vivo interactions between B cells and CD4⁺T cells that recognize a transgene-encoded autoantigen, hen egg lysozyme (HEL), using cells from mice trans-genic for immunoglobulin and T-cell receptor (TCR) genes. B cells that had not previously encountered HEL autoantigen (naive cells) were triggered into proliferation and antibody production upon interaction with antigen and HEL-specific CD4⁺T cells. By contrast, B cells that had been chronically exposed to HEL during their development and carried desensitized surface immunoglobulin (slg) antigen receptors⁹(anergic cells) did not produce antibody but instead were eliminated in the presence of HEL-specific CD4⁺T cells. CD95-deficient anergic B cells, however, were not eliminated by CD4⁺T cells and were triggered to proliferate. These findings identify a novel regulatory step for eliminating autoreactive B cells that seems unique in its dependence on CD95.