Epitopes described in "Islet-specific CTL cloned from a type 1 diabetes patient cause beta-cell destruction after engraftment into HLA-A2 transgenic NOD/scid/IL2RG null mice."

Article Authors:Wendy W J Unger; Todd Pearson; Joana R F Abreu; Sandra Laban; Arno R van der Slik; Sacha Mulder-van der Kracht; Michel G D Kester; Dave V Serreze; Leonard D Shultz; Marieke Griffioen; Jan Wouter Drijfhout; Dale L Greiner; Bart O Roep
Article Title:Islet-specific CTL cloned from a type 1 diabetes patient cause beta-cell destruction after engraftment into HLA-A2 transgenic NOD/scid/IL2RG null mice.
Reference Detail
Reference ID:1025272
Abstract:Despite increasing evidence that autoreactive CD8 T-cells are involved in both the initiation of type 1 diabetes (T1D) and the destruction of beta-cells, direct evidence for their destructive role in-vivo is lacking. To address a destructive role for autoreactive CD8 T-cells in human disease, we assessed the pathogenicity of a CD8 T-cell clone derived from a T1D donor and specific for an HLA-A2-restricted epitope of islet-specific glucose-6-phosphatase catalytic-subunit related protein (IGRP). HLA-A2/IGRP tetramer staining revealed a higher frequency of IGRP-specific CD8 T-cells in the peripheral blood of recent onset human individuals than of healthy donors. IGRP(265-273)-specific CD8 T-cells that were cloned from the peripheral blood of a recent onset T1D individual were shown to secrete IFN and Granzyme B after antigen-specific activation and lyse HLA-A2-expressing murine islets in-vitro. Lytic capacity was also demonstrated in-vivo by specific killing of peptide-pulsed target cells. Using the HLA-A2 NOD-scid IL2r(null) mouse model, HLA-A2-restricted IGRP-specific CD8 T-cells induced a destructive insulitis. Together, this is the first evidence that human HLA-restricted autoreactive CD8 T-cells target HLA-expressing beta-cells in-vivo, demonstrating the translational value of humanized mice to study mechanisms of disease and therapeutic intervention strategies.
Affiliations:Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Reference Type:Literature
PubMed ID:23155466
Journal:PLoS One
Journal Volume:7
Article Pages:e49213
Journal ISSN:1932-6203
Article Chemical List:Epitopes;HLA-A2 Antigen
Article MeSH List:Animals; CD8-Positive T-Lymphocytes(immunology; metabolism); Diabetes Mellitus, Type 1(genetics; immunology; metabolism); Epitopes(immunology; metabolism); HLA-A2 Antigen(genetics; immunology; metabolism); Humans; Insulin-Secreting Cells(immunology; metabolism); Mice; Mice, Inbred NOD; Mice, Transgenic; T-Lymphocytes, Cytotoxic(immunology; metabolism)
Curation Last Updated:2015-06-07 20:19:12