Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection

Abstract

Summary C-type lectin receptors sense a diversity of endogenous and exogenous ligands that may trigger differential responses. Here, we have found that human and mouse Mincle bind to a ligand released by Leishmania, a eukaryote parasite that evades an effective immune response. Mincle-deficient mice had milder dermal pathology and a tenth of the parasite burden compared to wild-type mice after Leishmania major intradermal ear infection. Mincle deficiency enhanced adaptive immunity against the parasite, correlating with increased activation, migration and priming by Mincle-deficient dendritic cells (DCs). Leishmania triggered a Mincle-dependent inhibitory axis characterized by SHP1 coupling to the FcRγ chain. Selective loss of SHP1 in CD11c+ cells phenocopies enhanced adaptive immunity to Leishmania. In conclusion, Leishmania shifts Mincle to an inhibitory ITAM (ITAMi) configuration that impairs DC activation. Thus, ITAMi can be exploited for immune evasion by a pathogen and may represent a paradigm for ITAM-coupled receptors sensing self and non-self.

M. tuberculosis -Initiated Human Mannose Receptor Signaling Regulates Macrophage Recognition and Vesicle Trafficking by FcRγ-Chain, Grb2, and SHP-1

“…MR knockdown in hMDMs significantly reduced SHP-1 recruitment to phagosomal membranes demonstrating the dependence on MR signaling. Our data do not support a direct interaction between SHP-1 and FcRγ-chain as recently reported by Iborra et al (Iborra et al, 2016) which studied Mincle-mediated inhibitory signaling events in murine GMCSF-treated bone marrow-derived cells suggesting receptor and/or mammalian cell differences.…”

Trehalose dimycolate interferes with FcγR-mediated phagosome maturation through Mincle, SHP-1 and FcγRIIB signalling

“…We therefore hypothesise that TDM-Mincle interaction activates SHP-1 to subsequently inhibit PI3K and phagosome maturation. Our study corroborates and extends the observation by Iborra and colleagues, which recently revealed the link between Mincle and SHP-1 during Leishmania infection [27]. These authors demonstrated that recognition of the parasites by Mincle triggers an inhibitory FcγR-SHP-1 axis in dendritic cells subsequently leading to down-regulation of Th 1 responses required for protective immunity to Leishmania parasites.…”

Anisakis pegreffii impacts differentiation and function of human dendritic cells

“…Which are the ligands in A. pegreffii that are involved in such immunomodulatory effects remains an open question. Recently, the C‐type lectin receptors, recognizing carbohydrate ligands, seem to play a key role in triggering immunosuppressive functions of DCs by helminths . Interestingly, Ani s 7, among the major allergens in A. pegreffii , is indeed a glycoprotein …”