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T Cell Tolerance Induced by Cross-Reactive TCR Ligands Can Be Broken by Superagonist Resulting in Anti-Inflammatory T Cell Cytokine Production¹

Center for Neurologic Diseases, Harvard Institute of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

Cross-reactive activation of potentially autoreactive T cells by high-affinity nonself ligands may be important in breaking self-tolerance in autoimmunity. In a mouse transgenic for a cross-reactive TCR, we have previously shown that a hyperstimulating altered peptide ligand, L144, induced unresponsiveness to the self peptide, proteolipid protein 139–151. In this study, we demonstrate that a superagonist ligand can break T cell tolerance induced by the lower affinity cognate Ag. T cells tolerant to the cognate ligand, Q144, responded to superagonist, L144, by proliferation and the production of mainly IL-4 and IL-10 in vitro. In contrast, T cells that were tolerized to the superagonist were unable to respond to any peptide that cross-reacted with the transgenic TCR. Low-dose immunization with the superagonist L144 was able to break tolerance to the cognate ligand in vivo and resulted in a blunted proliferative response with production of Th2 cytokines.

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