Cross-talk between ILC3 and BDCA1+ DC results in bi-directional activation via IL-1β

Innate lymphoid cells (ILCs) are crucial effectors of innate immunity and tissue remodelling but the physiological signals required by ILCs to exert their functions are only partially elucidated. The present study aimed at analysing the role of the interplay between ILCs and myeloid dendritic cells (DCs) in the contest of human tonsil inflammation. We found that, in vitro, tonsil-derived mDCs efficiently stimulated the proliferation of ILC3, but not ILC1 and ILC2, as assessed by Ki67 staining. In particular, between the two mDC subsets analysed, BDCA1+ DCs are mainly responsible of ILC3 proliferation; conversely, BDCA3+ DCs have only a modest effect. Upon co-culture with BDCA1+ DCs, ILC3 rapidly acquired the expression of natural cytotoxic receptors (NCR). Accordingly, the amount of Nkp44pos ILC3 in human tonsil correlated with the degree of inflammation. In addition, BDCA1+ DCs induced the production of large amount of cytokines, including IL-22, IL-8 and GM-CSF by ILC3. When compared to BDCA3+ DCs, BDCA1+ DCs were much stronger inducers of both ILC3 activation and cytokine production. On the other hand, ILC3 enhance the maturation of BDCA1+ DCs and stimulate them to produce IL-1β that appears to be critically involved in DC-mediated ILC3 proliferation, IL-22 production and, likely in a autocrine way, DC maturation. Finally, human ILC3 express DNAM-1 receptor that is involved in DC-mediated GM-CSF production by ILC3, upstream signal of IL-1β production by DCs. Altogether these data clearly shown that BDCA1+ DCs are particularly well suited to support ILC3 expansion and cytokine release. ILC3, in turn, activate mDCs suggesting a broader role of ILC3/mDC cooperation in regulating mucosal homeostasis or promoting pathological processes.