Role of antigen-presenting cells in mediating tolerance and autoimmunity

The mechanisms that determine whether receptor stimulation leads to lymphoc yte tolerance versus activation remain poorly understood. We have used rat insulin promoter (RIP)-gp/P14 double-transgenic mice expressing the: lympho cytic choriomeningitis virus (LCMV) glycoprotein (gp) on pancreatic beta-is let: cells together with T cells expressing an LCMV-gp-specific T cell rece ptor to assess the requirements for the induction of autoimmunity. Our stud ies have shown that administration of the gp peptide gp33 leads to the acti vation of P14-transgenic T cells, as measured by the upregulation of activa tion markers and the induction of effector cytotoxic activity. This treatme nt also leads to expansion and deletion of P14 T cells. Despite the inducti on of cytotoxic T lymphocyte activity, peptide administration is not suffic ient to induce diabetes. However, the administration of gp peptide together with an activating anti-CD40 antibody rapidly induces diabetes. These find ings suggest that the induction of tolerance versus autoimmunity is determi ned by resting versus activated antigen-presenting cells.