TY  - JOUR
AU  - Culina, Slobodan
AU  - Lalanne, Ana Ines
AU  - Afonso, Georgia
AU  - Cerosaletti, Karen
AU  - Pinto, Sheena
AU  - Sebastiani, Guido
AU  - Kuranda, Klaudia
AU  - Nigi, Laura
AU  - Eugster, Anne
AU  - Østerbye, Thomas
AU  - Maugein, Alicia
AU  - McLaren, James E
AU  - Ladell, Kristin
AU  - Larger, Etienne
AU  - Beressi, Jean-Paul
AU  - Lissina, Anna
AU  - Appay, Victor
AU  - Davidson, Howard W
AU  - Buus, Søren
AU  - Price, David A
AU  - Kuhn, Matthias
AU  - Bonifacio, Ezio
AU  - Battaglia, Manuela
AU  - Caillat-Zucman, Sophie
AU  - Dotta, Francesco
AU  - Scharfmann, Raphael
AU  - Kyewski, Bruno
AU  - Mallone, Roberto
AU  - Carel, Jean-Claude
AU  - Tubiana-Rufi, Nadia
AU  - Martinerie, Laetitia
AU  - Poidvin, Amélie
AU  - JacqzAigrain, Evelyne
AU  - Corvez, Laurence
AU  - Berruer, Véronique
AU  - Gautier, Jean-François
AU  - Baz, Baz
AU  - Haddadi, Nassima
AU  - Andreelli, Fabrizio
AU  - Amouyal, Chloé
AU  - Jaqueminet, Sophie
AU  - Bourron, Olivier
AU  - Dasque, Eric
AU  - Hartemann, Agnès
AU  - Lemoine-Yazigi, Amal
AU  - Dubois-Laforgue, Danièle
AU  - Travert, Florence
AU  - Feron, Marilyne
AU  - Rolland, Patrice
AU  - Vignali, Valérie
AU  - Marre, Michel
AU  - Chanson, Philippe
AU  - Briet, Claire
AU  - Guillausseau, Pierre-Jean
AU  - Ait-Bachir, Leila
AU  - Collet, Carole
AU  - Beziaud, Frédéric
AU  - Desforges-Bullet, Virginie
AU  - Petit-Aubert, Gwenaelle
AU  - Christin-Maitre, Sophie
AU  - Fève, Bruno
AU  - Vatier, Camille
AU  - Bourcigaux, Nathalie
AU  - Lautridou, Céline
AU  - Lahlou, Najiba
AU  - Bakouboula, Prissile
AU  - Elie, Caroline
AU  - Morel, Hélène
AU  - Treluyer, Jean-Marc
AU  - Gagnerault, Marie-Claude
AU  - Maillard, Claire
AU  - Jones, Anna
TI  - Islet-reactive CD8+ T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors.
JO  - Science immunology
VL  - 3
IS  - 20
SN  - 2470-9468
CY  - Washington, DC
PB  - AAAS
M1  - DKFZ-2018-00722
SP  - eaao4013 -
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:29429978
C2  - pmc:PMC5874133
DO  - DOI:10.1126/sciimmunol.aao4013
UR  - https://inrepo02.dkfz.de/record/136022
ER  -