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Innocuous IFNγ induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production
The role of Th17 cells in type I diabetes (TID) remains largely unknown. Glutamic acid decarboxylase (GAD) sequence 206–220 (designated GAD2) represents a late-stage epitope, but GAD2-specific T cell receptor transgenic T cells producing interferon γ (IFNγ) protect against passive TID. Because IFNγ...
Autores principales: | , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2008
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2234380/ https://www.ncbi.nlm.nih.gov/pubmed/18195074 http://dx.doi.org/10.1084/jem.20071878 |
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author | Jain, Renu Tartar, Danielle M. Gregg, Randal K. Divekar, Rohit D. Bell, J. Jeremiah Lee, Hyun-Hee Yu, Ping Ellis, Jason S. Hoeman, Christine M. Franklin, Craig L. Zaghouani, Habib |
author_facet | Jain, Renu Tartar, Danielle M. Gregg, Randal K. Divekar, Rohit D. Bell, J. Jeremiah Lee, Hyun-Hee Yu, Ping Ellis, Jason S. Hoeman, Christine M. Franklin, Craig L. Zaghouani, Habib |
author_sort | Jain, Renu |
collection | PubMed |
description | The role of Th17 cells in type I diabetes (TID) remains largely unknown. Glutamic acid decarboxylase (GAD) sequence 206–220 (designated GAD2) represents a late-stage epitope, but GAD2-specific T cell receptor transgenic T cells producing interferon γ (IFNγ) protect against passive TID. Because IFNγ is known to inhibit Th17 cells, effective presentation of GAD2 peptide under noninflammatory conditions may protect against TID at advanced disease stages. To test this premise, GAD2 was genetically incorporated into an immunoglobulin (Ig) molecule to magnify tolerance, and the resulting Ig-GAD2 was tested against TID at different stages of the disease. The findings indicated that Ig-GAD2 could not prevent TID at the preinsulitis phase, but delayed TID at the insulitis stage. More importantly, Ig-GAD2 sustained both clearance of pancreatic cell infiltration and β-cell division and restored normoglycemia when given to hyperglycemic mice at the prediabetic stage. This was dependent on the induction of splenic IFNγ that inhibited interleukin (IL)-17 production. In fact, neutralization of IFNγ led to a significant increase in the frequency of Th17 cells, and the treatment became nonprotective. Thus, IFNγ induced by an adjuvant free antigen, contrary to its usual inflammatory function, restores normoglycemia, most likely by localized bystander suppression of pathogenic IL-17–producing cells. |
format | Text |
id | pubmed-2234380 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-22343802008-07-21 Innocuous IFNγ induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production Jain, Renu Tartar, Danielle M. Gregg, Randal K. Divekar, Rohit D. Bell, J. Jeremiah Lee, Hyun-Hee Yu, Ping Ellis, Jason S. Hoeman, Christine M. Franklin, Craig L. Zaghouani, Habib J Exp Med Articles The role of Th17 cells in type I diabetes (TID) remains largely unknown. Glutamic acid decarboxylase (GAD) sequence 206–220 (designated GAD2) represents a late-stage epitope, but GAD2-specific T cell receptor transgenic T cells producing interferon γ (IFNγ) protect against passive TID. Because IFNγ is known to inhibit Th17 cells, effective presentation of GAD2 peptide under noninflammatory conditions may protect against TID at advanced disease stages. To test this premise, GAD2 was genetically incorporated into an immunoglobulin (Ig) molecule to magnify tolerance, and the resulting Ig-GAD2 was tested against TID at different stages of the disease. The findings indicated that Ig-GAD2 could not prevent TID at the preinsulitis phase, but delayed TID at the insulitis stage. More importantly, Ig-GAD2 sustained both clearance of pancreatic cell infiltration and β-cell division and restored normoglycemia when given to hyperglycemic mice at the prediabetic stage. This was dependent on the induction of splenic IFNγ that inhibited interleukin (IL)-17 production. In fact, neutralization of IFNγ led to a significant increase in the frequency of Th17 cells, and the treatment became nonprotective. Thus, IFNγ induced by an adjuvant free antigen, contrary to its usual inflammatory function, restores normoglycemia, most likely by localized bystander suppression of pathogenic IL-17–producing cells. The Rockefeller University Press 2008-01-21 /pmc/articles/PMC2234380/ /pubmed/18195074 http://dx.doi.org/10.1084/jem.20071878 Text en Copyright © 2008, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Articles Jain, Renu Tartar, Danielle M. Gregg, Randal K. Divekar, Rohit D. Bell, J. Jeremiah Lee, Hyun-Hee Yu, Ping Ellis, Jason S. Hoeman, Christine M. Franklin, Craig L. Zaghouani, Habib Innocuous IFNγ induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production |
title | Innocuous IFNγ induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production |
title_full | Innocuous IFNγ induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production |
title_fullStr | Innocuous IFNγ induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production |
title_full_unstemmed | Innocuous IFNγ induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production |
title_short | Innocuous IFNγ induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production |
title_sort | innocuous ifnγ induced by adjuvant-free antigen restores normoglycemia in nod mice through inhibition of il-17 production |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2234380/ https://www.ncbi.nlm.nih.gov/pubmed/18195074 http://dx.doi.org/10.1084/jem.20071878 |
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