title: Deoxyhypusine synthase promotes differentiation and proliferation of T helper type 1 (Th1) cells in autoimmune diabetes.
abstract: In type 1 diabetes, cytokines arising from immune cells cause islet β 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 non-obese diabetic (NOD) mouse model. Pre-diabetic NOD mice that received injections of the deoxyhypusine inhibitor N1-guanyl-1,7-diaminoheptane (GC7) demonstrated significantly improved glucose tolerance, more robust insulin secretion, and reduced insulitis compared with control animals. Analysis of tissues from treated mice revealed selective reductions in diabetogenic T helper type 1 (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 α 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 β cell function in type 1 diabetes.
authors.affiliation: From the Department of Pediatrics and the Herman B. Wells Center for Pediatric Research and.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Colvin
authors.forename: Bernhard
authors.initials: B
authors.lastname: Maier
authors.forename: David L
authors.initials: DL
authors.lastname: Morris
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Tersey
authors.forename: Raghavendra G
authors.initials: RG
authors.lastname: Mirmira
mesh_terms: D000818:Animals; D001786:Blood Glucose; D002454:Cell Differentiation; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology* / Q000201:enzymology / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D053645:Interleukin-2 Receptor alpha Subunit; C100667:N(1)-guanyl-1,7-diaminoheptane; D006147:Guanine; D000587:Oxidoreductases Acting on CH-NH Group Donors; C063507:deoxyhypusine synthase
keywords: Diabetes; Immunology; Islet; Mouse; T Cell