Innocuous IFNγ induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production

Renu Jain, Danielle Tartar, Randal K. Gregg, Rohit D. Divekar, J. Jeremiah Bell, Hyun Hee Lee, Ping Yu, Jason S. Ellis, Christine M. Hoeman, Craig L. Franklin, Habib Zaghouani

Research output: Contribution to journalArticle

142 Scopus citations

Abstract

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. JEM

Original languageEnglish (US)
Pages (from-to)207-218
Number of pages12
JournalJournal of Experimental Medicine
Volume205
Issue number1
DOIs
StatePublished - Jan 21 2008
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Jain, R., Tartar, D., Gregg, R. K., Divekar, R. D., Bell, J. J., Lee, H. H., Yu, P., Ellis, J. S., Hoeman, C. M., Franklin, C. L., & Zaghouani, H. (2008). Innocuous IFNγ induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production. Journal of Experimental Medicine, 205(1), 207-218. https://doi.org/10.1084/jem.20071878