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 type I diabetes by consistent epidemiology, and by feeding and tolerization studies in diabetes-prone rodents. Dietary BSA was suggested as the culprit because patients and relevant rodents have elevated anti-BSA Abs that precipitate the recently cloned protein, p69, from beta cell 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 fine specificity of these T cells, 2) delineate a homologous peptide sequence 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 and 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 concentrations. These findings imply that high-affinity self-peptide triggers anergy, whereas low-affinity mimicry Ag triggers proliferative expansion of these T cells. This implies a disease model in which mimicry Ag would rescue autoreactive cells from ablation by self-Ag.
Miyazaki
I
I
Hospital For Sick Children, Research Institute, University of Toronto, Ontario, Canada.
Cheung
R K
RK
Gaedigk
R
R
Hui
M F
MF
Van der Meulen
J
J
Rajotte
R V
RV
Dosch
H M
HM
D000293:Adolescent; D000595:Amino Acid Sequence; D001324:Autoantigens / Q000276:immunology*; D001483:Base Sequence; D015153:Blotting, Western; D002648:Child; D017635:Clonal Anergy / Q000276:immunology*; D003429:Cross Reactions; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008969:Molecular Sequence Data; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000276:immunology; D012710:Serum Albumin, Bovine / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014158:Transcription, Genetic
D001324:Autoantigens; C087054:ICA1 protein, human; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D012710:Serum Albumin, Bovine