The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) suppresses T-cell responses and promotes immune tolerance in mammalian pregnancy, tumour resistance, chronic infection, autoimmunity and allergic inflammation. 'Reverse signalling' and 'non-canonical activation' of the transcription factor nuclear factor-κB (NF-κB) characterize the peculiar events that occur in dendritic cells when T-cell-engaged ligands work as signalling receptors and culminate in the induction of IDO expression by dendritic cells in an inhibitor of NF-κB (IκB) kinase-α (IKKα)-dependent manner. In this Opinion article, we propose that IDO acts as a bridge between dendritic cells and CD4+ regulatory T cells, and that regulatory T cells use reverse signalling and non-canonical NF-κB activation for effector function and self-propagation. This mechanism may also underlie the protective function of glucocorticoids in pathological conditions.
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We thank G. Andrielli for help with the original art work. Support for the work in our laboratory came in part from grants from the Juvenile Diabetes Research Foundation (U.G. and P.P.) and the Italian Association for Cancer Research (P.P.).
The authors declare no competing financial interests.
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Puccetti, P., Grohmann, U. IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-κB activation. Nat Rev Immunol 7, 817–823 (2007). https://doi.org/10.1038/nri2163
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