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Diabetes. 2017 Mar;66(3):710-721. doi: 10.2337/db16-0846. Epub 2016 Dec 5.

Interferon-γ Limits Diabetogenic CD8+ T-Cell Effector Responses in Type 1 Diabetes.

Author information

1
Department of Animal Sciences, University of Florida, Gainesville, FL jdriver@ufl.edu dave.serreze@jax.org.
2
The Jackson Laboratory, Bar Harbor, ME.
3
Department of Animal Sciences, University of Florida, Gainesville, FL.
4
Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
5
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
6
The Jackson Laboratory, Bar Harbor, ME jdriver@ufl.edu dave.serreze@jax.org.

Abstract

Type 1 diabetes development in the NOD mouse model is widely reported to be dependent on high-level production by autoreactive CD4+ and CD8+ T cells of interferon-γ (IFN-γ), generally considered a proinflammatory cytokine. However, IFN-γ can also participate in tolerance-induction pathways, indicating it is not solely proinflammatory. This study addresses how IFN-γ can suppress activation of diabetogenic CD8+ T cells. CD8+ T cells transgenically expressing the diabetogenic AI4 T-cell receptor adoptively transferred disease to otherwise unmanipulated NOD.IFN-γnull , but not standard NOD, mice. AI4 T cells only underwent vigorous intrasplenic proliferation in NOD.IFN-γnull recipients. Disease-protective IFN-γ could be derived from any lymphocyte source and suppressed diabetogenic CD8+ T-cell responses both directly and through an intermediary nonlymphoid cell population. Suppression was not dependent on regulatory T cells, but was associated with increased inhibitory STAT1 to STAT4 expression levels in pathogenic AI4 T cells. Importantly, IFN-γ exposure during activation reduced the cytotoxicity of human-origin type 1 diabetes-relevant autoreactive CD8+ T cells. Collectively, these results indicate that rather than marking the most proinflammatory lymphocytes in diabetes development, IFN-γ production could represent an attempted limitation of pathogenic CD8+ T-cell activation. Thus, great care should be taken when designing possible diabetic intervention approaches modulating IFN-γ production.

PMID:
27920091
PMCID:
PMC5319715
DOI:
10.2337/db16-0846
[Indexed for MEDLINE]
Free PMC Article

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