T-CELL ACTIVATION AND ANERGY TO ISLET-CELL ANTIGEN IN TYPE-I DIABETES

Early exposure to cow milk proteins was linked to the development of t ype I diabetes by consistent epidemiology, and by feeding and toleriza tion studies in diabetes-prone rodents. Dietary BSA was suggested as t he culprit because patients and relevant rodents have elevated anti-BS A Abs that precipitate the recently cloned protein, p69, from beta cel l lysates. A total of 68 of 78 children with recent onset diabetes had BSA-reactive T cells at the time of diagnosis. Here we 1) map the fin e specificity of these T cells, 2) delineate a homologous peptide sequ ence near the N-terminus of p69, and 3) demonstrate T cell recognition of this p69 sequence (T cell epitope p69, Tep69) by patient T cells. The Tep69 sequence is conserved in p69 of patients and diabetes-prone rodents. Whereas BSA triggers T cell proliferation, recombinant p69 an d a synthetic Tep69 peptide induce early stages of T cell activation ( IL-2R transcription) but insufficient IL-2 production and thus anergy. Exogenous IL-2 overrides anergy and allows proliferative expansion of p69-responsive T cells. In mixing experiments, p69 and Tep69 peptide prevented proliferative responses to BSA even at 100-fold smaller conc entrations. These findings imply that high-affinity self-peptide trigg ers anergy, whereas low-affinity mimicry Ag triggers proliferative exp ansion of these T cells. This implies a disease model in which mimicry Ag would rescue autoreactive cells from ablation by self-Ag.