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.
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 IFNγ 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 IL2rγ(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.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Wendy W J
authors.initials: WW
authors.lastname: Unger
authors.forename: Todd
authors.initials: T
authors.lastname: Pearson
authors.forename: Joana R F
authors.initials: JR
authors.lastname: Abreu
authors.forename: Sandra
authors.initials: S
authors.lastname: Laban
authors.forename: Arno R
authors.initials: AR
authors.lastname: van der Slik
authors.forename: Sacha Mulder-van
authors.initials: SM
authors.lastname: der Kracht
authors.forename: Michel G D
authors.initials: MG
authors.lastname: Kester
authors.forename: Dave V
authors.initials: DV
authors.lastname: Serreze
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.forename: Marieke
authors.initials: M
authors.lastname: Griffioen
authors.forename: Jan Wouter
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.forename: Bart O
authors.initials: BO
authors.lastname: Roep
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
chemical_list: D000939:Epitopes; D015789:HLA-A2 Antigen