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

Slobodan Culina 1, 2, 3 Ana Inés Lalanne 1, 2, 3 Georgia Afonso 1, 2, 3 Karen Cerosaletti 4 Sheena Pinto 5 Guido Sebastiani 6 Klaudia Kuranda 1, 2, 3 Laura Nigi 6 Anne Eugster 7 Thomas Østerbye 8 Alicia Maugein 1, 2, 3 James Mclaren 9 Kristin Ladell 9 Etienne Larger 1, 2, 10, 3, 11 Jean-Paul Beressi 12 Anna Lissina 13, 14 Victor Appay 13, 14 Howard Davidson 15 Søren Buus 8 David Price 9, 16 Matthias Kuhn 17 Ezio Bonifacio 7 Manuela Battaglia 18 Sophie Caillat-Zucman 19, 20 Francesco Dotta 6 Raphael Scharfmann 1, 2 Bruno Kyewski 5 Roberto Mallone 1, 2, 10, 3, *
* Corresponding author
1 IC UM3 (UMR 8104 / U1016) - Institut Cochin
2 USPC - Université Sorbonne Paris Cité
3 UPD5 - Université Paris Descartes - Paris 5
4 Translational Research Program [Seattle, WA, USA]
5 Division of Developmental Immunology [Heidelberg, Germany]
6 Diabetes Unit - Department of Medicine, Surgery and Neuroscience [Siena, Italy]
7 Medical Faculty - CRTD-DFG Research Center for Regenerative Therapies Dresden [Dresden, Germany]
8 Department of Immunology and Microbiology [Copenhagen]
9 School of Medicine - Division of Infection and Immunity [Cardiff, UK]
10 Service de diabétologie [CHU Cochin]
11 APHP - Assistance publique - Hôpitaux de Paris (AP-HP)
12 Service de Diabétologie [CH Versailles André Mignot, Le Chesnay]
13 CIMI - Centre d'Immunologie et de Maladies Infectieuses
14 DHU FAST - Département Hospitalo-Universitaire Fight Ageing and STress [UPMC, Paris]
15 BDC - Barbara Davis Center for Childhood Diabetes
16 Vaccine Research Center [Bethesda, MD, USA]
17 Medical Faculty - Institut für Medizinische Informatik und Biometrie [Dresden, Germany]
18 Diabetes Research Institute [Milan, Italy]
19 UMR_S 561 - Immunologie, génétique et traitement des maladies métaboliques et du diabète
20 Laboratoire Jean Dausset d'Immunologie et d'Histocompatibilité [AP-HP Hôpital Saint-Louis]
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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CNRS | USPC | UNIV-PARIS5 | SORBONNE-UNIVERSITE | CIMI | SU-MEDECINE | UNIV-PARIS7

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Slobodan Culina, Ana Inés Lalanne, Georgia Afonso, Karen Cerosaletti, Sheena Pinto, et al.. Islet-reactive CD8 + T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors. Science Immunology, American Association for the Advancement of Science, 2018, 3 (20), ⟨10.1126/sciimmunol.aao4013⟩. ⟨inserm-01918833⟩

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