title: In vivo effects of cytokines on pancreatic beta-cells in models of type I diabetes dependent on CD4(+) T lymphocytes.
abstract: CD4(+) T cells can actively kill beta-cells in type I diabetes as well as help CD8(+) T cells become cytolytic. Cytokines have the potential to kill beta-cells, or upregulate Fas on beta-cells, and increase their susceptibility to FasL. We investigated the direct effects of cytokines on beta-cells in perforin-deficient non-obese diabetic (NOD) mice and NOD4.1 TCR transgenic mice, two models in which CD8(+) T cells play a less dominant role. Inhibiting the effects of cytokines by the overexpression of suppressor of cytokine signalling-1 (SOCS1) in beta-cells did not reduce diabetes or insulitis in perforin-deficient NOD, NOD4.1 or interleukin (IL)-1 receptor-deficient NOD4.1 mice. SOCS1 overexpression prevented Fas upregulation on NOD4.1 beta-cells, but did not prevent islet destruction because SOCS1 transgenic islets were killed when grafted into NOD4.1.scid mice. Likewise, Fas-deficient NOD.lpr islets were destroyed in NOD4.1 mice. Although blocking the effects of interferon (IFN)gamma on beta-cells did not affect diabetes in NOD4.1 mice, global deficiency of IFNgammaR2 reduced diabetes and insulitis, suggesting that IFNgamma is involved in CD4(+) T-cell activation or migration. Our data show that beta-cells under attack by CD4(+) T cells are not destroyed by the effects of cytokines including IFNgamma and IL-1 or Fas-dependent cytotoxicity.
authors.affiliation: St Vincent's Institute, Fitzroy, Melbourne, Victoria, Australia.
authors.forename: Eveline
authors.initials: E
authors.lastname: Angstetra
authors.forename: Kate L
authors.initials: KL
authors.lastname: Graham
authors.forename: Sarah
authors.initials: S
authors.lastname: Emmett
authors.forename: Nadine L
authors.initials: NL
authors.lastname: Dudek
authors.forename: Rima
authors.initials: R
authors.lastname: Darwiche
authors.forename: Rochelle
authors.initials: R
authors.lastname: Ayala-Perez
authors.forename: Janette
authors.initials: J
authors.lastname: Allison
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
authors.forename: Thomas W H
authors.initials: TW
authors.lastname: Kay
authors.forename: Helen E
authors.initials: HE
authors.lastname: Thomas
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000494:pharmacology*; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D054353:Perforin / Q000172:deficiency
chemical_list: D016207:Cytokines; D054353:Perforin