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.
Authors Unger WW, Pearson T, Abreu JR, Laban S, van der Slik AR, der Kracht SM, Kester
MG, Serreze DV, Shultz LD, Griffioen M, Drijfhout JW, Greiner DL, Roep BO
Submitted By Submitted Externally on 7/10/2013
Status Published
Journal PLoS ONE
Year 2012
Date Published 1/15/2013
Volume : Pages 7 : e49213
PubMed Reference 23155466
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

Investigators with authorship
Leonard ShultzJackson Laboratory