Islet-reactive CD8 ⁺ T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors

The human leukocyte antigen-A2 (HLA-A2)-restricted zinc transporter 8_186-194 (ZnT8_186-194) and other islet epitopes elicit interferon-γ secretion by CD8⁺ T cells preferentially in type 1 diabetes (T1D) patients compared with controls. We show that clonal ZnT8_186-194-reactive CD8⁺ T cells express private T cell receptors and display equivalent functional properties in T1D and healthy individuals. Ex vivo analyses further revealed that CD8⁺ T cells reactive to ZnT8_186-194 and other islet epitopes circulate at similar frequencies and exhibit a predominantly naïve phenotype in age-matched T1D and healthy donors. Higher frequencies of ZnT8_186-194-reactive CD8⁺ T cells with a more antigen-experienced phenotype were detected in children versus adults, irrespective of disease status. Moreover, some ZnT8_186-194-reactive CD8⁺ T cell clonotypes were found to cross-recognize a <i>Bacteroides stercoris</i> mimotope. Whereas ZnT8 was poorly expressed in thymic medullary epithelial cells, variable thymic expression levels of islet antigens did not modulate the peripheral frequency of their cognate CD8⁺ T cells. In contrast, ZnT8_186-194-reactive cells were enriched in the pancreata of T1D patients versus nondiabetic and type 2 diabetic individuals. Thus, islet-reactive CD8⁺ T cells circulate in most individuals but home to the pancreas preferentially in T1D patients. We conclude that the activation of this common islet-reactive T cell repertoire and progression to T1D likely require defective peripheral immunoregulation and/or a proinflammatory islet microenvironment.