title: Killer Treg restore immune homeostasis and suppress autoimmune diabetes in prediabetic NOD mice.
abstract: We hypothesized that regulatory T cells (Treg) effectively target diabetogenic cells, and reinforcing their killing capacity will attenuate the course of disease. For proof of concept, Fas-ligand (FasL) protein was conjugated to CD25(+) Treg (killer Treg) to simulate the physiological mechanism of activation-induced cell death. Cytotoxic and suppressive activity of killer Treg was superior to naïve Treg in vitro. Administration of 3-4 × 10(6) Treg prevented hyperglycemia in 65% prediabetic NOD females, however only killer Treg postponed disease onset by 14 weeks. CD25(+) Treg homed to the pancreas and regional lymph nodes of prediabetic NOD females, proliferated and ectopic FasL protein induced apoptosis in CD25(-) T cells in situ. This mechanism of pathogenic cell debulking is specific to killer Treg, as FasL-coated splenocytes have no immunomodulatory effect, and only killer Treg prevent the disease in 80% of NOD.SCID recipients of effector:suppressor T cells (10:1 ratio). All immunomodulated mice displayed increased fractional expression of FoxP3 in the pancreas and draining lymph nodes, which was accompanied by CD25 only in recipients of killer Treg. A therapeutic intervention that uses the affinity of Treg to reduce the pathogenic load has long-term consequences: arrest of destructive insulitis in mice with established disease prior to β-cell extinction.
authors.affiliation: Frankel Laboratory, Center for Stem Cell Research, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Kaminitz
authors.forename: Esma S
authors.initials: ES
authors.lastname: Yolcu
authors.forename: Jerry
authors.initials: J
authors.lastname: Stein
authors.forename: Isaac
authors.initials: I
authors.lastname: Yaniv
authors.forename: Haval
authors.initials: H
authors.lastname: Shirwan
authors.forename: Nadir
authors.initials: N
authors.lastname: Askenasy
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D053222:Fas Ligand Protein / Q000276:immunology; D005260:Female; D006706:Homeostasis / Q000276:immunology*; 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*
chemical_list: D053222:Fas Ligand Protein