In vivo effects of cytokines on pancreatic beta-cells in models of type I diabetes dependent on CD4(+) T lymphocytes.
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.
Angstetra
Eveline
E
St Vincent's Institute, Fitzroy, Melbourne, Victoria, Australia.
Graham
Kate L
KL
Emmett
Sarah
S
Dudek
Nadine L
NL
Darwiche
Rima
R
Ayala-Perez
Rochelle
R
Allison
Janette
J
Santamaria
Pere
P
Kay
Thomas W H
TW
Thomas
Helen E
HE
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
D016207:Cytokines; D054353:Perforin