Publications & Reports

Immunotherapy with Costimulatory Dendritic Cells To Control Autoimmune Inflammation.

O'Sullivan BJ, Pai S, Street S, An X, Macdonald KP, Wong M, Strutton G, Gerondakis S, Steptoe RJ, Fazekas de St Groth B, Hill GR, Thomas R
University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia;

Abstract

Costimulation-deficient dendritic cells (DCs) prevent autoimmune disease in mouse models. However, autoimmune-prone mice and humans fail to control expansion of peripheral autoreactive effector memory T cells (T(EMs)), which resist immunoregulation by costimulation-deficient DCs. In contrast, activation of DC costimulation may be coupled with regulatory capacity. To test whether costimulatory DCs control T(EMs) and attenuate established autoimmune disease, we used RelB-deficient mice, which have multiorgan inflammation, expanded peripheral autoreactive T(EMs), and dysfunctional Foxp3(+) regulatory T cells (Tregs) cells and conventional DCs. T(EMs) were regulated by Foxp3(+) Tregs when costimulated by CD3/CD28-coated beads or wild-type DCs but not DCs deficient in RelB or CD80/CD86. After transfer, RelB and CD80/CD86-sufficient DCs restored tolerance and achieved a long-term cure of autoimmune disease through costimulation of T(EM) and Foxp3(+) Treg IFN-gamma production, as well as induction of IDO by host APCs. IDO was required for regulation of T(EMs) and suppression of organ inflammation. Our data challenge the paradigm that costimulation-deficient DCs are required to regulate established autoimmune disease to avoid T(EM) activation and demonstrate cooperative cross-talk between costimulatory DCs, IFN-gamma, and IDO-dependent immune regulation. IFN-gamma and IDO activity may be good surrogate biomarkers measured against clinical efficacy in trials of autoimmune disease immunoregulation.

Publication

  • Journal: Journal of Immunology
  • Published: 15/10/2011
  • Volume: 187
  • Issue: 8
  • Pagination: 4018-4030