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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...

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Autores principales: 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
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2008
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.
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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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