title: Killer Treg cells ameliorate inflammatory insulitis in non-obese diabetic mice through local and systemic immunomodulation.
abstract: Treg cells endowed with enhanced killing activity through decoration with Fas-ligand (FasL) protein (killer Treg) have been effective in delay of hyperglycemia in prediabetic non-obese diabetic (NOD) mice. In this study, we assessed the therapeutic efficacy of these cells, harvested from age-matched euglycemic NOD donors, on the course of disease in new-onset diabetics. One dose of 4 × 10(6) killer Treg cells stabilized blood glucose associated with increased insulin levels in 5 of 9 mice and partially reversed the severity of islet inflammation, whereas naive Treg cells did not modulate the course of disease significantly. Killer Treg cells were shown to operate through induction of cell apoptosis within the pancreatic lymph nodes, resulting in reduced efficiency of adoptive disease transfer to NOD/SCID recipients. A second mechanism of action consisted of increased fractions of CD4(+)CD25(-)FoxP3(+) T cells in the pancreas and all lymphoid organs. Immunomodulation with FasL rather than Treg cells enhanced the expression of CD25 and FoxP3 in the thymus, suggesting a possible contribution of thymic output to prolonged stabilization of the glucose levels. Autologous Treg cells evolve as excellent vehicles for targeted delivery of FasL as an immunomodulatory protein, which delete pathogenic cells at the site of inflammation and induce systemic dominance of suppressor subsets.
authors: Frankel Laboratory, Center for Stem Cell Research, Schneider Children's Medical Center of Israel, Petach Tikva 49202, Israel.
authors: Ayelet
authors: A
authors: Kaminitz
authors: Esma S
authors: ES
authors: Yolcu
authors: Keren
authors: K
authors: Mizrahi
authors: Haval
authors: H
authors: Shirwan
authors: Nadir
authors: N
authors: Askenasy
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000473:pathology*; D056747:Immunomodulation; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
keywords: Fas-ligand; NOD mice; destructive insulitis; killer Treg; new-onset diabetes; regulatory T cell