IDO-orchestrated crosstalk between pDCs and Tregs inhibits autoimmunity

Lippens, Carla; Duraes, Fernanda V.; Dubrot, Juan; Brighouse, Dale; Lacroix, Mathilde; Irla, Magali; Aubry-Lachainaye, Jean-Pierre; Reith, Walter; Mandl, Judith N.; Hugues, Stéphanie

During EAE, mice lacking MHCII on pDCs developed exacerbated disease, with increased IFN-γ and reduced TGF-β production in LNs compared to WT mice [23]. MHCII-deficient pDCs nevertheless still exhibit a strong impairment in IDO expression upon EAE. Therefore, neither IFN-γ, nor TGF-β, was sufficient to induce IDO in absence of MHCII expression by pDCs. In addition, we show that pDCs tolerogenicity in EAE context is dependent on their expression of IDO. First, in IDO deficient mice, encephalitogenic T cell frequency was increased, and as a consequence, disease was exacerbated. Second, adoptively transferred Tregs inhibited EAE only when isolated from actively MOG35–55 immunized WT, but not IDO−/− mice, suggesting that Tregs need to be primed in an IDO sufficient microenvironment to acquire their suppressive functions. Third, in LNs, IDO was predominantly expressed by pDCs, in both naïve and EAE mice. Finally, in an experimental setting in which we controlled IDO expression exclusively in pDCs, we observed an inhibition of EAE, as well as an increase in suppressive Tregs, only when pDCs expressed IDO. Notably, Treg induced after Ag-specific interaction with IDO+ pDCs are necessary to inhibit pathogenic T cells in LNs. Altogether, our results demonstrate that IDO expression by pDCs is required for the generation of suppressive Tregs that, upon Ag-specific activation, competently inhibit encephalitogenic T cells during EAE priming phase. In conclusion, we showed that naïve pDCs are high IDO expressors in the LN, a property acquired after a cross-talk with Foxp3+ Tregs. By expressing IDO, pDCs become competent to confer suppressive functions to Tregs in the context of EAE, where Ag-presenting IDO+ pDCs promote suppressive Tregs that inhibit the priming of encephalitogenic Th1 and Th17 cells and dampen CNS autoimmunity. Future investigations will determine whether other pDC features and functions, apart from IDO expression, are impacted following interactions with Tregs. Together, our data have identified a new regulatory role for Tregs in shaping Ag-presenting pDC functions towards tolerogenicity in autoimmunity.