Cargando…
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
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 ass...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498321/ https://www.ncbi.nlm.nih.gov/pubmed/23155466 http://dx.doi.org/10.1371/journal.pone.0049213 |
_version_ | 1782249824934952960 |
---|---|
author | Unger, Wendy W. J. Pearson, Todd Abreu, Joana R. F. Laban, Sandra van der Slik, Arno R. der Kracht, Sacha Mulder-van Kester, Michel G. D. Serreze, Dave V. Shultz, Leonard D. Griffioen, Marieke Drijfhout, Jan Wouter Greiner, Dale L. Roep, Bart O. |
author_facet | Unger, Wendy W. J. Pearson, Todd Abreu, Joana R. F. Laban, Sandra van der Slik, Arno R. der Kracht, Sacha Mulder-van Kester, Michel G. D. Serreze, Dave V. Shultz, Leonard D. Griffioen, Marieke Drijfhout, Jan Wouter Greiner, Dale L. Roep, Bart O. |
author_sort | Unger, Wendy W. J. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3498321 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-34983212012-11-15 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 Unger, Wendy W. J. Pearson, Todd Abreu, Joana R. F. Laban, Sandra van der Slik, Arno R. der Kracht, Sacha Mulder-van Kester, Michel G. D. Serreze, Dave V. Shultz, Leonard D. Griffioen, Marieke Drijfhout, Jan Wouter Greiner, Dale L. Roep, Bart O. PLoS One Research Article 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. Public Library of Science 2012-11-14 /pmc/articles/PMC3498321/ /pubmed/23155466 http://dx.doi.org/10.1371/journal.pone.0049213 Text en © 2012 Unger et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Unger, Wendy W. J. Pearson, Todd Abreu, Joana R. F. Laban, Sandra van der Slik, Arno R. der Kracht, Sacha Mulder-van Kester, Michel G. D. Serreze, Dave V. Shultz, Leonard D. Griffioen, Marieke Drijfhout, Jan Wouter Greiner, Dale L. Roep, Bart O. 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 |
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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498321/ https://www.ncbi.nlm.nih.gov/pubmed/23155466 http://dx.doi.org/10.1371/journal.pone.0049213 |
work_keys_str_mv | AT ungerwendywj isletspecificctlclonedfromatype1diabetespatientcausebetacelldestructionafterengraftmentintohlaa2transgenicnodscidil2rgnullmice AT pearsontodd isletspecificctlclonedfromatype1diabetespatientcausebetacelldestructionafterengraftmentintohlaa2transgenicnodscidil2rgnullmice AT abreujoanarf isletspecificctlclonedfromatype1diabetespatientcausebetacelldestructionafterengraftmentintohlaa2transgenicnodscidil2rgnullmice AT labansandra isletspecificctlclonedfromatype1diabetespatientcausebetacelldestructionafterengraftmentintohlaa2transgenicnodscidil2rgnullmice AT vanderslikarnor isletspecificctlclonedfromatype1diabetespatientcausebetacelldestructionafterengraftmentintohlaa2transgenicnodscidil2rgnullmice AT derkrachtsachamuldervan isletspecificctlclonedfromatype1diabetespatientcausebetacelldestructionafterengraftmentintohlaa2transgenicnodscidil2rgnullmice AT kestermichelgd isletspecificctlclonedfromatype1diabetespatientcausebetacelldestructionafterengraftmentintohlaa2transgenicnodscidil2rgnullmice AT serrezedavev isletspecificctlclonedfromatype1diabetespatientcausebetacelldestructionafterengraftmentintohlaa2transgenicnodscidil2rgnullmice AT shultzleonardd isletspecificctlclonedfromatype1diabetespatientcausebetacelldestructionafterengraftmentintohlaa2transgenicnodscidil2rgnullmice AT griffioenmarieke isletspecificctlclonedfromatype1diabetespatientcausebetacelldestructionafterengraftmentintohlaa2transgenicnodscidil2rgnullmice AT drijfhoutjanwouter isletspecificctlclonedfromatype1diabetespatientcausebetacelldestructionafterengraftmentintohlaa2transgenicnodscidil2rgnullmice AT greinerdalel isletspecificctlclonedfromatype1diabetespatientcausebetacelldestructionafterengraftmentintohlaa2transgenicnodscidil2rgnullmice AT roepbarto isletspecificctlclonedfromatype1diabetespatientcausebetacelldestructionafterengraftmentintohlaa2transgenicnodscidil2rgnullmice |