| First Author | Driver JP | Year | 2017 |
| Journal | Diabetes | Volume | 66 |
| Issue | 3 | Pages | 710-721 |
| PubMed ID | 27920091 | Mgi Jnum | J:246468 |
| Mgi Id | MGI:5924501 | Doi | 10.2337/db16-0846 |
| Citation | Driver JP, et al. (2017) Interferon-gamma Limits Diabetogenic CD8+ T-Cell Effector Responses in Type 1 Diabetes. Diabetes 66(3):710-721 |
| abstractText | 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-gamma (IFN-gamma), generally considered a proinflammatory cytokine. However, IFN-gamma can also participate in tolerance-induction pathways, indicating it is not solely proinflammatory. This study addresses how IFN-gamma 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-gammanull , but not standard NOD, mice. AI4 T cells only underwent vigorous intrasplenic proliferation in NOD.IFN-gammanull recipients. Disease-protective IFN-gamma 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-gamma 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-gamma 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-gamma production. |
