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

ABSTRACT: The human leukocyte antigen-A2 (HLA-A2)-restricted zinc transporter 8186-194 (ZnT8186-194) and other islet epitopes elicit interferon-? 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.

SUBMITTER: Culina S

PROVIDER: S-EPMC5874133 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Culina Slobodan S Lalanne Ana Ines AI Afonso Georgia G Cerosaletti Karen K Pinto Sheena S Sebastiani Guido G Kuranda Klaudia K Nigi Laura L Eugster Anne A Østerbye Thomas T Maugein Alicia A McLaren James E JE Ladell Kristin K Larger Etienne E Beressi Jean-Paul JP Lissina Anna A Appay Victor V Davidson Howard W HW Buus Søren S Price David A DA Kuhn Matthias M Bonifacio Ezio E Battaglia Manuela M Caillat-Zucman Sophie S Dotta Francesco F Scharfmann Raphael R Kyewski Bruno B Mallone Roberto R

Science immunology 20180201 20

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<sup ...[more]

PMID: 29429978

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Project description:Aims/hypothesisIslet prohormone-processing enzymes convert peptide hormone precursors to mature hormones. Defective beta cell prohormone processing and the release of incompletely processed peptide hormones are observed prior to the onset of diabetes, yet molecular mechanisms underlying impaired prohormone processing during the development of diabetes remains largely unknown. Previous studies have shown that prohormone convertase 1/3 (PC1/3) protein and mRNA expression levels are reduced in whole islets from donors with type 1 diabetes, although whether PC1/3-mediated prohormone processing in alpha and beta cells is disrupted in type 1 diabetes remained to be explored. Herein, we aimed to analyse the expression of PC1/3 in islets from non-diabetic donors, autoantibody-positive donors and donors diagnosed with type 1 diabetes or type 2 diabetes.MethodsImmunostaining and high-dimensional image analysis were performed on pancreatic sections from a cross-sectional cohort of 54 donors obtained from the Network for Pancreatic Organ Donors with Diabetes (nPOD) repository, to evaluate PC1/3 expression patterns in islet alpha, beta and delta cells at different stages of diabetes.ResultsAlpha and beta cell morphology were altered in donors with type 1 diabetes, including decreased alpha and beta cell size. As expected, the insulin-positive and PC1/3-positive areas in the islets were both reduced, and this was accompanied by a reduced percentage of PC1/3-positive and insulin-positive/PC1/3-positive cells in islets. PC1/3 and insulin co-localisation was also reduced. The glucagon-positive area, as well as the percentage of glucagon-positive and glucagon-positive/PC1/3-positive cells in islets, was increased. PC1/3 and glucagon co-localisation was also increased in donors with type 1 diabetes. The somatostatin-positive cell area and somatostatin staining intensity were elevated in islets from donors with recent-onset type 1 diabetes.Conclusions/interpretationOur high-resolution histomorphological analysis of human pancreatic islets from donors with and without diabetes has uncovered details of the cellular origin of islet prohormone peptide processing defects. Reduced beta cell PC1/3 and increased alpha cell PC1/3 in islets from donors with type 1 diabetes pinpointed the functional deterioration of beta cells and the concomitant potential increase in PC1/3 usage for prohormone processing in alpha cells during the pathogenesis of type 1 diabetes. Our finding of PC1/3 loss in beta cells may inform the discovery of new prohormone biomarkers as indicators of beta cell dysfunction, and the finding of elevated PC1/3 expression in alpha cells may encourage the design of therapeutic targets via leveraging alpha cell adaptation in diabetes.

Dataset Information

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

Publications

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

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