题名：Deoxyhypusine Synthase Promotes Differentiation and Proliferation of Th1 Cells in Autoimmune Diabetes.
作者：COLVIN SC; MAIER B; MORRIS DL; TERSEY SA; MIRMIRA RG;
来源：J Biol Chem. 2013 Nov 6. [ IF= 0.00 ] ]
摘要：In type 1 diabetes, cytokines arising from immune cells cause islet beta cell
dysfunction even before overt hyperglycemia. Deoxyhypusine synthase catalyzes the
crucial hypusine modification of the factor eIF5A, which promotes the translation
of a subset of mRNAs involved in cytokine responses. Here, we tested the
hypothesis that deoxyhypusine synthase and, secondarily, hypusinated eIF5A
contribute to the pathogenesis of type 1 diabetes using the NOD mouse model.
Pre-diabetic NOD mice that received injections of the deoxyhypusine inhibitor GC7
demonstrated significantly improved glucose tolerance, more robust insulin
secretion, and reduced insulitis compared to control animals. Analysis of tissues
from treated mice revealed selective reductions in diabetogenic Th1 cells in the
pancreatic lymph nodes, a primary site of antigen presentation. Isolated mouse
CD90.2+ splenocytes stimulated in vitro with anti-CD3/anti-CD28 and IL-2 to mimic
autoimmune T cell activation exhibited proliferation and differentiation of CD4+
T cell subsets (Th1, Th17, and Treg), but those treated with the deoxyhypusine
synthase inhibitor GC7 showed a dose-dependent block in T cell proliferation with
selective reduction in Th1 cells, similar to that observed in NOD mice.
Inhibition of deoxyhypusine synthase blocked post-transcriptional expression of
CD25, the high affinity IL-2 receptor alpha chain. Our results suggest a
previously unrecognized role for deoxyhypusine synthase in promoting T cell
proliferation and differentiation via regulation of CD25. Inhibition of
deoxyhypusine synthase may provide a strategy for reducing diabetogenic Th1 cells
and preserving beta cell function in type 1 diabetes.