Dr. rer nat Lara Linnemann (Hamburg / DE), Jennifer Antwi (Hamburg / DE), Dr. Vinayaga Gnanapragassam (Hannover / DE), Timm Ramcke (Hamburg / DE), Prof. Dr. Bernd Lepenies (Hannover / DE), Prof. Dr. Minka Breloer (Hamburg / DE)
Abstract text
Objectives
One quarter of the human population is infected with helminths, large multicellular parasites, that are controlled in the context of a type 2 immune response. Using Strongyloides ratti infection in mice, we aim to analyse the role of C-type lectin receptors (CLR), an ancient family of innate pattern recognition receptors, in the initiation and modulation of protective type 2 immunity to helminths.
Methods
Screening a CLR-hFc library, we found yet unidentified S. ratti derived ligand(s), engaging Macrophage inhibitory C type lectin receptor (MINCLE) and further signalling into a MINCLE reporter cell line. We used a MINCLE-deficient mouse to analyse this interaction and its effects in vitro and in vivo.
Results & Conclusions
Strikingly, the loss of this CLR in MINCLE-deficient mice resulted in reduced intestinal parasite burden when compared to wildtype mice, suggesting absence of the CLR did not impair but improved the host defence immune response. Parameters of Type 2 immunity like mucosal mast cell activation, S. ratti specific Th2 cell responses, protective memory and also the intestinal microbiota were unchanged in MINCLE-deficient mice. However, an increase in MINCLE+ cell populations, like eosinophils, neutrophils and dendritic cells, was observed in the lungs and intestine, offering a possible target for a MINCLE-ligand. Additionally, in vitro stimulation of MINCLE+, but not MINCLE-deficient, macrophages and dendritic cells with a baseline concentration of the MINCLE agonist TDB and increasing concentrations of S. ratti lysate, lead to a dose dependent reduction of TDB-induced TNF production. By contrast, production of TDB-induced IL-6 and IL-10 were synergistically increased by co-stimulation with S. ratti lysate. We are currently investigating the nature of the putative S. ratti -derived MINCLE ligand and its modulatory effects on the hosts immune response.