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

We next evaluated whether IDO was implicated in the regulation of encephalitogenic T cell priming during EAE. Knowing that MHCII deficient pDCs exhibit impaired IDO expression both in steady-state and during EAE (Fig. 2, Fig. 3C), we analysed EAE development in WT → WT, pIII + IV−/− → WT and IDO−/− → WT chimeric mice. As before, disease was exacerbated in mice lacking MHCII on pDCs (pIII + IV−/− → WT) compared to control WT → WT animals (Fig. 4A). This could be consequent to either an absence of Ag-presentation by pDCs and/or a resulting defect in IDO expression by pDCs from pIII + IV−/− → WT mice. Consistently with previously published data [51], [52], mice deficient for IDO (IDO−/− → WT) developed aggravated EAE compared to WT controls. Importantly, clinical scores of IDO−/− → WT were comparable to mice lacking MHCII on pDCs (Fig. 4A). Notably, we did not notice any significant impact of IDO deficiency during EAE induced by transferring MOG35–55-specific 2D2 CD4+ effector T cells (Fig. S5), suggesting a critical role for IDO in the modulation of pathogenic T cell priming in SLOs during EAE. To confirm this hypothesis, we measured effector cytokine production by T cells before clinical symptom appearance (day 9) in IDO−/− → WT, pIII + IV−/− → WT and WT → WT chimeras. Elevated IFN-γ and IL-17 producing encephalitogenic CD4+ T cell frequencies were observed in LNs of IDO deficient mice (IDO−/− → WT) and mice lacking MHCII expression by pDCs (pIII + IV−/− → WT) compared to WT → WT controls, (Fig. 4B). Foxp3+CD25hi Treg proliferation was impaired in pIII + IV−/− → WT mice, whereas it was unaffected in IDO−/− → WT mice (Fig. 4C, left), showing that MHCII-mediated Ag presentation, but not IDO expression by pDCs, promoted Foxp3+ Treg proliferation. The proliferation of Foxp3+ Tregs exhibiting a suppressive phenotype (CD103+ICOS+) [53] (Fig. 4C middle), as well as the frequency of IL-10 expressing Foxp3+ Tregs (Fig. 4C right), were significantly decreased in LNs from both pIII + IV−/− → WT and IDO−/− → WT compared to WT → WT mice. Our results identify a new role for IDO in impacting the ability of Tregs to suppress encephalitogenic T cells in LNs.