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

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-? (IFN-?), generally considered a proinflammatory cytokine. However, IFN-? can also participate in tolerance-induction pathways, indicating it is not solely proinflammatory. This study addresses how IFN-? 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-?^null , but not standard NOD, mice. AI4 T cells only underwent vigorous intrasplenic proliferation in NOD.IFN-?^null recipients. Disease-protective IFN-? 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-? 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-? 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-? production.

SUBMITTER: Driver JP 

PROVIDER: S-EPMC5319715 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature