Autoimmune male, but not female, BXSB/MpJ mice resist the induction of tolerance to human gammaglobulin (HGG). To better define the cellular basis for this abnormality, we have compared in vitro the functional activity of antigen-presenting cells between tolerant-resistant male and susceptible female mice, and evaluated in vivo the immunological status of HGG-specific T helper cells in male BXSB mice after the treatment with monomeric deaggregated HGG (DHGG). Our results indicated that there were no significant differences in the ability of male and female antigen-presenting cells to present HGG to either male or female HGG-specific immune T blasts. Further, thymic cells from DHGG-treated male BXSB mice failed to support anti-HGG antibody responses when adoptively transferred with non-treated bone marrow cells, and that draining lymph node cells from male as well as female BXSB mice treated with DHGG prior to the challenge of immunogenic aggregated HGG (AHGG) were unable to exhibit the proliferation upon in vitro restimulation with AHGG. This indicates that HGG-specific T helper cells were indeed tolerized in tolerant-resistant male BXSB mice by the treatment with DHGG. In contrast, when the tolerance induction was inhibited by bacterial lipopolysaccharides, HGG-specific T helper cells from such mice exhibited a marked proliferation upon in vitro restimulation with AHGG. These results suggest that the cellular defect in the abnormal resistance to tolerance induction to HGG in male BXSB mice resides neither in the antigen-presenting cells nor in the HGG-specific T helper cells, and that the mechanism responsible for this abnormality in male BXSB mice is basically different from that involved when tolerance is overcome by lipopolysaccharide.