The goal of this study was to examine the functional responses and tolerance susceptibility of T lymphocytes from mice of the autoimmune strain, MRL/lpr. A population of autoreactive CD4+ T cells can be readily expanded from the lymphoid tissues of young lpr mice. Lines of IL-2-producing autoreactive and alloreactive lpr and alloreactive +/+ T cells were developed to study their responses to tolerance-inducing stimuli. Culture of +/+ T cells with high concentrations of immobilized anti-CD3 antibody induces both functional anergy and apoptosis. By contrast, lpr-derived T cell lines are relatively resistant to anergy and apoptosis. The implications of these findings for the development of autoimmunity, and the possible role of the Fas Ag in determining resistance or susceptibility to tolerance, are discussed.