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

Whether pDCs exhibit tolerogenic or immunogenic APC functions in different immunogical context is an important matter of debate, and might depend on their own ability to produce inflammatory cytokines, as suggested by previous studies [9]. pDC tolerogenicity has been correlated to their expression of IDO in different settings [24], [31], [35]. In a mouse model of skin inflammation, IDO was induced in pDCs either after IFN-γ or TGF-β stimulation, the first pathway promoting IDO enzymatic activity-dependent tryptophan depletion, the second one implicating IDO phosphorylation and subsequent Treg induction [35]. Here we show that already in steady-state, pDCs are the major expressors of IDO in LNs. We further provide evidence that IDO expression in naïve pDCs is regulated through Ag-specific MHCII-restricted interaction with Foxp3+ Tregs. First, pDCs isolated from TCR tg mice in which CD4+ T cells all recognize a non-expressed antigenic peptide, exhibited substantially reduced IDO expression, independently of the self-reactivity of the TCR. Second, in absence of an existing Treg population in those TCR tg mice, LN pDCs exhibited a dramatic reduction in IDO expression. In addition, pDCs isolated from LN of Treg-deficient Scurfy mice expressed very little IDO mRNA. We cannot exclude that in Scurfy mice, the non-Treg CD4+ T cell population, which is strongly biased towards a pro-inflammatory autoimmune repertoire compared to WT mice, might impact IDO expression. Nevertheless, IDO expression by pDCs from T cell deficient mice was induced after co-culture with a CD4+ T cells only when the later contained a descent Treg population. In addition, IDO restoration was further dependent on the presence of the cognate antigenic peptide. The contribution of Treg in inducing IDO in pDCs has been suggested before [56], however without real evidence for a requirement of MHCII-restricted, Ag-specific interactions between pDCs and Tregs. Whether a particular Treg subpopulation would be specifically involved in this crosstalk with pDCs to induce IDO expression, and possibly the expression of other genes as well, remains to be determined. A role for IL-10 has been demonstrated in IDO expression stabilization [57]. Therefore, it is possible that IL-10 producing Tregs might be more competent to induce IDO up-regulation in pDCs. Our results reinforce the idea that Treg exhibit their Ag-specific immunomodulatory roles by impacting different cellular targets, not only by inhibiting effector T cells [58], inducing tumor-associated DC death [59] but also by promoting pDC tolerogenic functions. Future investigations will determine whether other pDC-specific tolerogenic features similarly depend on interactions with Tregs.