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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Slobodan Culina
  • Ana Ines Lalanne
  • Georgia Afonso
  • Karen Cerosaletti
  • Sheena Pinto
  • Guido Sebastiani
  • Klaudia Kuranda
  • Laura Nigi
  • Anne Eugster
  • Alicia Maugein
  • James E. McLaren
  • Kristin Ladell
  • Etienne Larger
  • Jean-Paul Beressi
  • Anna Lissina
  • Victor Appay
  • Howard W. Davidson
  • David A. Price
  • Matthias Kuhn
  • Ezio Bonifacio
  • Manuela Battaglia
  • Sophie Caillat-Zucman
  • Francesco Dotta
  • Raphael Scharfmann
  • Bruno Kyewski
  • Roberto Mallone
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.
Original languageEnglish
Article numbereaao4013
JournalScience immunology
Issue number20
Publication statusPublished - 2018

ID: 210065725