T-CELLS INVOLVED IN HUMAN AUTOIMMUNE-DISEASE ARE RESISTANT TO TOLERANCE INDUCTION

Deletion of potentially self-reactive T-cell clones during intrathymic development provides an important mechanism of preventing autoreactiv ity. However, some potentially damaging cells may escape this process. Recent evidence suggests that these cells may be rendered 'anergic', that is, nonresponsive to Ag, in the absence of cell death. Such a mec hanism may be particularly important in maintaining tolerance to organ -specific self Ag that are not expressed in the thymus. If so, the eme rgence of T cells resistant to anergy induction might be expected to r esult in autoimmune disease. It has previously been shown that anergy can be induced in human T cells in vitro by exposure to specific targe t peptide or bacterial enterotoxins in the absence of Ag-presenting ce lls. We have recently defined the antigenic specificity of multiple T- cell clones present at the site of a human organ-specific autoimmune d isease, Graves' thyroiditis (Graves disease). In the current work, thy roid-derived T cells recognizing residues 535-551 of the thyroid tissu e-specific enzyme, TPO3 have been used to examine whether cells active ly involved in the autoimmune process are resistant to anergy inductio n, as defined by anergy induction with in vitro systems. Two systems w ere used. First, supraimmunogenic concentrations of peptide 535-551 (u p to 1 mg/ml) failed to significantly anergize these T cells in the ab sence of APC. In addition, the bacterial enterotoxin SED that could st imulate these T cells in the presence of APC, failed to induce anergy when APC were not present. T cells from the peripheral blood of the sa me individual, in contrast, were anergizable with bacterial enterotoxi ns, using the same protocol. These results suggest that thyroid-infilt rating autoantigen-reactive T cells are refractory to induction of ane rgy, and the possibility is raised that this deficiency may be of impo rtance in the development of autoimmunity.