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.