title: Interleukin-1β produced in response to islet autoantigen presentation differentiates T-helper 17 cells at the expense of regulatory T-cells: Implications for the timing of tolerizing immunotherapy.
abstract: OBJECTIVE
  The effectiveness of tolerizing immunotherapeutic strategies, such as anti-CD40L or dendritic cells (DCs), is greater when administered to young nonobese diabetic (NOD) mice than at peak insulitis. RelB(lo) DCs, generated in the presence of an nuclear factor-κB inhibitor, induce T-regulatory (Treg) cells and suppress inflammation in a model of rheumatoid arthritis. Interleukin (IL)-1β is overexpressed in humans and mice at risk of type 1 diabetes, dysregulates Treg cells, and accelerates diabetes in NOD mice. We investigated the relationship between IL-1β production and the response to RelB(lo) DCs in the prediabetic period.
  
  
  METHODS
  We injected RelB(lo) DCs subcutaneously into 4- or 14-week-old NOD mice and tracked the incidence of diabetes and effect on Treg cell function. We measured the expression of proinflammatory cytokines by stimulated splenocytes and unstimulated islets from mice of different ages and strains and proliferative and cytokine responses of T effectors to Treg in vitro.
  
  
  RESULTS
  Tolerizing RelB(lo) DCs significantly inhibited diabetes progression when administered to 4-week-old but not 14-week-old mice. IL-1β production by NOD splenocytes and mRNA expression by islets increased from 6 to 16 weeks of age when major histocompatibility complex (MHC)-restricted islet antigen presentation to autoreactive T-cells occurred. IL-1 reduced the capacity of Treg cells to suppress effector cells and promoted their conversion to Th17 cells. RelB(lo) DCs exacerbated the IL-1-dependent decline in Treg function and promoted Th17 conversion.
  
  
  CONCLUSIONS
  IL-1β, generated by islet-autoreactive cells in MHC-susceptible mice, accelerates diabetes by differentiating Th17 at the expense of Treg. Tolerizing DC therapies can regulate islet autoantigen priming and prevent diabetes, but progression past the IL-1β/IL-17 checkpoint signals the need for other strategies.
authors.affiliation: The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Bertin-Maghit
authors.forename: Dimeng
authors.initials: D
authors.lastname: Pang
authors.forename: Brendan
authors.initials: B
authors.lastname: O'Sullivan
authors.forename: Shannon
authors.initials: S
authors.lastname: Best
authors.forename: Emily
authors.initials: E
authors.lastname: Duggan
authors.forename: Sanjoy
authors.initials: S
authors.lastname: Paul
authors.forename: Helen
authors.initials: H
authors.lastname: Thomas
authors.forename: Thomas W H
authors.initials: TW
authors.lastname: Kay
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Harrison
authors.forename: Raymond
authors.initials: R
authors.lastname: Steptoe
authors.forename: Ranjeny
authors.initials: R
authors.lastname: Thomas
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001786:Blood Glucose / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D003713:Dendritic Cells / Q000637:transplantation; D003920:Diabetes Mellitus / Q000097:blood; D007108:Immune Tolerance; D007167:Immunotherapy / Q000379:methods*; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D020381:Interleukin-17 / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000276:immunology / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000473:pathology / Q000503:physiopathology; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D051841:Transcription Factor RelB / Q000276:immunology
chemical_list: D001324:Autoantigens; D001786:Blood Glucose; D016207:Cytokines; D007328:Insulin; D020381:Interleukin-17; D053583:Interleukin-1beta; C497594:Relb protein, mouse; D051841:Transcription Factor RelB