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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, Lalanne, Ana Ines, Afonso, Georgia, Cerosaletti, Karen, Pinto, Sheena, Sebastiani, Guido, Kuranda, Klaudia, Nigi, Laura, Eugster, Anne, Østerbye, Thomas, Maugein, Alicia, McLaren, James, Ladell, Kristin, Larger, Etienne, Beressi, Jean-Paul, Lissina, Anna, Appay, Victor, Davidson, Howard W., Buus, Søren, Price, David, Kuhn, Matthias, Bonifacio, Ezio, Battaglia, Manuela, Caillat-Zucman, Sophie, Dotta, Francesco, Scharfmann, Raphael, Kyewski, Bruno and Mallone, Roberto 2018. Islet-reactive CD8+ T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors. Science Immunology 3 (20) , eaao4013. 10.1126/sciimmunol.aao4013

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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 redominantly 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

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Association for the Advancement of Science
ISSN: 2470-9468
Funders: Wellcome Trust, JDRF, NIH, ERC, Aviesan/Astra Zeneca, SocieÌteÌ Francophone du DiabeÌte, Agence Nationale de la Recherche, Fondation pour la Recherche MeÌdicale, Helmsley Charitable Trust
Date of First Compliant Deposit: 15 February 2018
Date of Acceptance: 4 December 2017
Last Modified: 28 Apr 2018 10:25
URI: http://orca.cf.ac.uk/id/eprint/109138

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