Interferon-γ Limits Diabetogenic CD8(+) T-Cell Effector Responses in Type 1 Diabetes.
Document Type
Article
Publication Date
3-2017
JAX Location
Reprint Collection
JAX Source
Diabetes 2017 Mar; 66(3):710-721.
Volume
66
Issue
3
First Page
710
Last Page
721
ISSN
1939-327X
PMID
27920091
DOI
https://doi.org/10.2337/db16-0846
Grant
DK46266, DK97535
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-γ(null) , but not standard NOD, mice. AI4 T cells only underwent vigorous intrasplenic proliferation in NOD.IFN-γ(null) 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. Diabetes 2017 Mar; 66(3):710-721.
Recommended Citation
Driver J,
Racine J,
Ye C,
Lamont D,
Newby B,
Leeth CM,
Chapman HD,
Brusko T,
Chen Y,
Mathews C,
Serreze DV.
Interferon-γ Limits Diabetogenic CD8(+) T-Cell Effector Responses in Type 1 Diabetes. Diabetes 2017 Mar; 66(3):710-721.