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Anergy Induction by Dimeric TCR Ligands¹

Heiner Appel^*, Nilufer P. Seth^*, Laurent Gauthier^* and Kai W. Wucherpfennig^2,*,

^* Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, and Department of Neurology, Harvard Medical School, Boston, MA 02115

T cells that recognize particular self Ags are thought to be important in the pathogenesis of autoimmune diseases. In multiple sclerosis, susceptibility 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 the specificity of their TCR, we expressed a soluble dimeric DR2-IgG fusion protein with a bound peptide from myelin basic protein (MBP). Soluble, dimeric 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 anergic T cells were initially viable, but became susceptible to late apoptosis due to insufficient production of cytokines. Dimerization of the TCR with bivalent MHC class II/peptide complexes therefore allows the induction of anergy in human CD4⁺ T cells with a defined MHC/peptide specificity.

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