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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 8186–194 (ZnT8186–194) 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, ZnT8186–194-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.
Abstract
The human leukocyte antigen–A2 (HLA-A2)–restricted zinc transporter 8186–194 (ZnT8186–194) 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 ZnT8186–194-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 ZnT8186–194 and other islet epitopes circulate at similar frequencies and exhibit a predominantly naïve phenotype in age-matched T1D and healthy donors. Higher frequencies of ZnT8186–194-reactive CD8+ T cells with a more antigen-experienced phenotype were detected in children versus adults, irrespective of disease status. Moreover, some ZnT8186–194-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, ZnT8186–194-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.
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