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* Division of Immune Regulation, and
Division of Experimental Medicine, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121;
Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute, Royal Melbourne Hospital, Parkville, Australia;
Institut National de la Santé et de la Recherche Médicale, Unité 561, Hopital Cochin-Saint Vincent de Paul, Paris, France; and
¶ Diabetes Center, University of California, San Francisco, CA 94143
Self peptide-MHC ligands create and maintain the mature T cell repertoire by positive selection in the thymus and by homeostatic proliferation in the periphery. A low affinity/avidity interaction among T cells, self peptides, and MHC molecules has been suggested for these events, but it remains unknown whether or how this self-interaction is involved in tolerance and/or autoimmunity. Several lines of evidence implicate the glutamic acid decarboxylase 65 (GAD-65) peptide, p524–543, as a specific, possibly low affinity, stimulus for the spontaneously arising, diabetogenic T cell clone BDC2.5. Interestingly, BDC2.5 T cells, which normally are unresponsive to p524–543 stimulation, react to the peptide when provided with splenic APC obtained from mice immunized with the same peptide, p524–543, but not, for example, with hen egg white lysozyme. Immunization with p524–543 increases the susceptibility of the NOD mice to type 1 diabetes induced by the adoptive transfer of BDC2.5 T cells. In addition, very few CFSE-labeled BDC2.5 T cells divide in the recipient’s pancreas after transfer into a transgenic mouse that overexpresses GAD-65 in B cells, whereas they divide vigorously in the pancreas of normal NOD recipients. A special relationship between the BDC2.5 clone and the GAD-65 molecule is further demonstrated by generation of a double-transgenic mouse line carrying both the BDC2.5 TCR and GAD-65 transgenes, in which a significant reduction of BDC2.5 cells in the pancreas has been observed, presumably due to tolerance induction. These data suggest that unique and/or altered processing of self Ags may play an essential role in the development and expansion of autoreactive T cells.
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