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

To investigate the role of pDC-induced Treg in EAE pathogenesis, we have induced EAE in mice lacking Treg and MHCII expression by pDCs. We backcrossed DEREG mice, in which Foxp3+ Tregs can be selectively depleted using diphtheria toxin (DT) injection [36], with pIII + IV−/− mice and generated DEREGxpIII + IV−/− → WT chimeras (Supplementary Fig. 4 A–C). In untreated mice, as previously described [23], EAE was exacerbated (Supplementary Fig. 4D) when pDCs did not express MHCII. Moreover, EAE clinical course was similarly aggravated in DEREG → WT treated with DT and DEREGxpIII + IV−/− → WT chimeras injected or not with DT (Supplementary Fig. 4D). Encephalitogenic Th1 and Th17 CD4+ T cell frequencies were increased in DT-injected DEREG → WT and DEREGxpIII + IV−/− → WT mice compared to un-injected DEREG → WT mice (Supplementary Fig. 4E). This demonstrates that the depletion of Tregs and the absence of MHCII expression by pDCs similarly enhance pathogenic T cell priming and disease severity. Altogether, our data show that pDC-instructed Tregs inhibit the priming of encephalitogenic T cells in LNs during EAE.