Faculty Collaboration Database

Interferon-γ Limits Diabetogenic CD8⁺ T-Cell Effector Responses in Type 1 Diabetes. Diabetes 2017 Mar;66(3):710-721

Date

12/07/2016

Pubmed ID

27920091

Pubmed Central ID

PMC5319715

DOI

10.2337/db16-0846

Scopus ID

2-s2.0-85019616155 (requires institutional sign-in at Scopus site)   23 Citations

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.

Author List

Driver JP, Racine JJ, Ye C, Lamont DJ, Newby BN, Leeth CM, Chapman HD, Brusko TM, Chen YG, Mathews CE, Serreze DV

Author

Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adoptive Transfer
Animals
CD8-Positive T-Lymphocytes
Cells, Cultured
Diabetes Mellitus, Type 1
Female
Humans
Interferon-gamma
Lymphocyte Activation
Mice
Mice, Inbred NOD
Mice, Transgenic
RNA, Messenger
Receptors, Antigen, T-Cell
Reverse Transcriptase Polymerase Chain Reaction
STAT1 Transcription Factor
STAT4 Transcription Factor
Spleen
T-Lymphocytes, Regulatory