Interferon-γ Limits Diabetogenic CD8
| Autor: | John P, Driver, Jeremy J, Racine, Cheng, Ye, Deanna J, Lamont, Brittney N, Newby, Caroline M, Leeth, Harold D, Chapman, Todd M, Brusko, Yi-Guang, Chen, Clayton E, Mathews, David V, Serreze |
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| Rok vydání: | 2016 |
| Předmět: |
Reverse Transcriptase Polymerase Chain Reaction
Receptors Antigen T-Cell Mice Transgenic CD8-Positive T-Lymphocytes STAT4 Transcription Factor Lymphocyte Activation Adoptive Transfer T-Lymphocytes Regulatory Interferon-gamma Mice Diabetes Mellitus Type 1 STAT1 Transcription Factor Mice Inbred NOD Animals Humans Female RNA Messenger Immunology and Transplantation Cells Cultured Spleen |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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