The myeloid C-type lectin receptor Mincle is a multifunctional sensor in immunity and homeostasis

Abstract

C-type lectin receptors (CLRs) are versatile platforms that sense a diversity of endogenous and exogenous ligands that may trigger differential responses. A prototypical example of this adaptability is the myeloid CLR Mincle. Classically viewed as an activating receptor, Mincle responds to several “non-self” ligands derived from pathogens contributing in most cases to the generation of immunity against the infection. However, Mincle-sensing of “non-self” ligands can also lead to immunosuppression directly favouring an anti-inflammatory response, or indirectly inhibiting heterologous receptors signalling. Here, we have found that human and mouse Mincle bind to a ligand released by Leishmania, a eukaryote parasite that effectively evades the immune system. Mincle-deficient mice had less pathology and lower parasite burden compared to wild-type mice after Leishmania major infection. Mincle deficiency enhanced adaptive immunity against the parasite, correlating with increased activation and migration of Mincle-deficient dendritic cells (DCs). Leishmania triggered a Mincle-dependent inhibitory axis characterized by SHP1 coupling to the FcRγ chain. In conclusion, Leishmania shifts Mincle to an inhibitory ITAM configuration that favours pathogen-mediated immune scape impairing DC activation. On the other hand, we have found that Mincle detects mucosa-associated commensals. Interaction of commensals with Mincle triggered DC activation through the classical ITAM configuration characterized by Syk coupling to the FcRγ chain. Mincle sensing of commensals in Peyer´s patches induced IL-6 and IL-23p19 expression and regulated intestinal Th17 cells and IL-17-secreting innate lymphoid cells (ILCs). These cells produce IL-17 and IL-22 that are critical for maintenance of the intestinal barrier function. Consequently, Mincle-deficient or CD11c-Cre Sykflox/flox mice showed impaired production of intestinal antimicrobial peptides and IgA, resulting in increased systemic translocation of gut microbiota and liver inflammation. Thus, sensing of commensals by Mincle reinforces intestinal immune barrier and promotes host-microbiota mutualism, preventing systemic inflammation. Our work supports the notion that Mincle can couple to an activating or to an inhibitory ITAM configuration depending on the nature of the ligand.