Immunotherapy with costimulatory dendritic cells to control autoimmune inflammation

O'Sullivan, Brendan J., Pai, Saparna, Street, Shayna, An, Xiayou, Macdonald, Kelli P. A., Wong, Michelle, Strutton, Geoffrey, Gerondakis, Steve, Steptoe, Raymond J., Fazekas de St Groth, Barbara, Hill, Geoffrey R. and Thomas, Ranjeny (2011) Immunotherapy with costimulatory dendritic cells to control autoimmune inflammation. Journal of Immunology, 187 7: 4018-4030. doi:10.4049/jimmunol.1101727

Author O'Sullivan, Brendan J.
Pai, Saparna
Street, Shayna
An, Xiayou
Macdonald, Kelli P. A.
Wong, Michelle
Strutton, Geoffrey
Gerondakis, Steve
Steptoe, Raymond J.
Fazekas de St Groth, Barbara
Hill, Geoffrey R.
Thomas, Ranjeny
Title Immunotherapy with costimulatory dendritic cells to control autoimmune inflammation
Journal name Journal of Immunology   Check publisher's open access policy
ISSN 0022-1767
Publication date 2011-10-01
Sub-type Article (original research)
DOI 10.4049/jimmunol.1101727
Volume 187
Issue 7
Start page 4018
End page 4030
Total pages 14
Place of publication United States
Publisher American Association of Immunologists
Collection year 2012
Language eng
Formatted 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 (TEMs), 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 TEMs and attenuate established autoimmune disease, we used RelB-deficient mice, which have multiorgan inflammation, expanded peripheral autoreactive TEMs, and dysfunctional Foxp3+ regulatory T cells (Tregs) cells and conventional DCs. TEMs 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 TEM and Foxp3+ Treg IFN-γ production, as well as induction of IDO by host APCs. IDO was required for regulation of TEMs and suppression of organ inflammation. Our data challenge the paradigm that costimulation-deficient DCs are required to regulate established autoimmune disease to avoid TEM activation and demonstrate cooperative cross-talk between costimulatory DCs, IFN-γ, and IDO-dependent immune regulation. IFN-γ and IDO activity may be good surrogate biomarkers measured against clinical efficacy in trials of autoimmune disease immunoregulation.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
Institute for Molecular Bioscience - Publications
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Created: Tue, 20 Sep 2011, 14:00:29 EST by Professor Ranjeny Thomas on behalf of Institute for Molecular Bioscience