Innocuous IFNgamma 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 gamma (IFNgamma) protect against passive TID. Because IFNgamma 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 beta-cell division and restored normoglycemia when given to hyperglycemic mice at the prediabetic stage. This was dependent on the induction of splenic IFNgamma that inhibited interleukin (IL)-17 production. In fact, neutralization of IFNgamma led to a significant increase in the frequency of Th17 cells, and the treatment became nonprotective. Thus, IFNgamma 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.
Jain
Renu
R
Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212, USA.
Tartar
Danielle M
DM
Gregg
Randal K
RK
Divekar
Rohit D
RD
Bell
J Jeremiah
JJ
Lee
Hyun-Hee
HH
Yu
Ping
P
Ellis
Jason S
JS
Hoeman
Christine M
CM
Franklin
Craig L
CL
Zaghouani
Habib
H
D000818:Animals; D000941:Antigens / Q000737:chemistry*; D001786:Blood Glucose / Q000378:metabolism*; D000939:Epitopes / Q000737:chemistry; D005786:Gene Expression Regulation; D006943:Hyperglycemia / Q000235:genetics* / Q000517:prevention & control; D007371:Interferon-gamma / Q000378:metabolism*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008954:Models, Biological; D010641:Phenotype; D011994:Recombinant Proteins
D000941:Antigens; D001786:Blood Glucose; D000939:Epitopes; D020381:Interleukin-17; D011994:Recombinant Proteins; D007371:Interferon-gamma