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

  1. Ranjeny Thomas1
  1. 1The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia;
  2. 2Queensland Clinical Trials and Biostatistics Centre, School of Population Health, The University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia;
  3. 3Islet Biology Laboratory, St. Vincent's Institute, Melbourne, Australia;
  4. 4Autoimmunity and Transplantation Division, Walter and Eliza Hall Institute, Melbourne, Australia.
  1. Corresponding author: Ranjeny Thomas, ranjeny.thomas{at}uq.edu.au.
  1. R.S. and R.T. contributed equally to this article.

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. RelBlo 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 RelBlo DCs in the prediabetic period.

RESEARCH DESIGN AND METHODS We injected RelBlo 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 RelBlo 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. RelBlo 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.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • Received January 22, 2010.
  • Accepted October 13, 2010.

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  1. Diabetes vol. 60 no. 1 248-257
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