title: Interferon-γ 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-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-γnullrecipients. 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.
authors.affiliation: Department of Animal Sciences, University of Florida, Gainesville, FL jdriver@ufl.edu dave.serreze@jax.org.
authors.forename: John P
authors.initials: JP
authors.lastname: Driver
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Racine
authors.affiliation: Department of Animal Sciences, University of Florida, Gainesville, FL.
authors.forename: Cheng
authors.initials: C
authors.lastname: Ye
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME.
authors.forename: Deanna J
authors.initials: DJ
authors.lastname: Lamont
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Brittney N
authors.initials: BN
authors.lastname: Newby
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Leeth
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME.
authors.forename: Harold D
authors.initials: HD
authors.lastname: Chapman
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Brusko
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Yi-Guang
authors.initials: YG
authors.lastname: Chen
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Clayton E
authors.initials: CE
authors.lastname: Mathews
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME jdriver@ufl.edu dave.serreze@jax.org.
authors.forename: David V
authors.initials: DV
authors.lastname: Serreze
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; C494080:Stat1 protein, mouse; C494091:Stat4 protein, mouse; D007371:Interferon-gamma