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

At home in the pancreas: Type 1 diabetes (T1D) is associated with enrichment of autoreactive CD8⁺ T cells that target destruction of pancreatic islets. Culina et al. studied islet-reactive CD8⁺ T cells reactive to the zinc transporter 8_186–194 (ZnT8_186–194) and other islet epitopes in healthy individuals and T1D patients, which showed similar functionality and similar frequencies and naïve phenotypes in the peripheral circulation across both groups. In contrast, ZnT8_186–194-reactive CD8⁺ T cells were enriched in the pancreas of T1D patients relative to healthy controls and showed cross-reactivity to an epitope from the commensal Bacteroides stercoris. These results indicate that incomplete central tolerance may allow the survival of these islet-reactive CD8⁺ T cells in the periphery, and that proinflammatory conditions in the islets can contribute to T1D progression. 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 Bacteroides stercoris 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. [ABSTRACT FROM AUTHOR]