Tolerance induction in mice by antibodies to T-cell epitopes

CD4/DR3 mice lack murine cd4 but express human CD4 specifically on helper T cells, and HLA-DR3 as its natural counter ligand (CD4/DR3 mice). The injection of these mice with anti-human CD4 prior to immunization with tetanus toxoid (TT, day 0) totally blocked the formation of specific Abs. When these mice were left untreated for at least 30 days, and were then re-exposed with TT, but in the absence of anti-human CD4, they consistently failed to induce specific antibodies (long-term unresponsiveness). Importantly, the concurrent injection of TT and anti-human CD4 at day 0, followed by another two anti-CD4 treatments also led to tolerant animals indicating that tolerance was inducible as late as the antigen exposure is provided. We demonstrate a limited ability of spleen cells to respond to TT in vitro indicating that T cells are essentially involved in the maintenance of tolerance. These data show for that the human CD4 coreceptor may mediate tolerance-inducing signals when triggered by an appropriate ligand in vivo.