Anergy induction by dimeric TCR ligands

T cells that recognize particular self Ags are thought to be important in t he pathogenesis of autoimmune diseases. In multiple sclerosis, susceptibili ty is associated with HLA-DR2, which can present myelin-derived peptides to CD4(+) T cells. To generate molecules that target such T cells based on th e specificity of their TCR, we expressed a soluble dimeric DR2-IgG fusion p rotein with a bound peptide from myelin basic protein (MBP). Soluble, dimer ic DR2/MBP peptide complexes activated MBP-specific T cells in the absence of signals from costimulatory or adhesion molecules. This initial signaling through the TCR rendered the T cells unresponsive (anergic) to subsequent activation by peptide-pulsed APCs. Fluorescent labeling demonstrated that a nergic T cells were initially viable, but became susceptible to late apopto sis due to insufficient production of cytokines. Dimerization of the TCR wi th bivalent MHC class II/peptide complexes therefore allows the induction o f anergy inhuman CD4(+) T cells with a defined MHC/peptide specificity.