Allergy protection mediated by Lactococcus lactis G121-stimulated dendritic cells requires endosomal acidification and activation through TLR13
Introduction: Epidemiological studies show that traditional cattle farming environment during fetal development and in early childhood reduces the incidence of allergies later in life. A variety of bacterial strains including Lactococcus lactis G121 have been isolated from cowsheds and proven to be allergy-protective in various mouse models. Up to now, the identity of mediators of the allergy-protective effect of L. lactis G121 is largely lacking.
Objectives: Identification of the central mechanisms and receptors by which L. lactis G121 induces an allergy-protective immune response.
Material and Methods: Challenge-induced cytokine release from in vitro cultures of human monocyte-derived dendritic cells (moDCs), from co-cultures of moDCs with autologous naïve CD4+ T-cells as well as from mouse bone marrow-derived dendritic cells (BMDCs) was analyzed. For the in vivo experiments, an OVA mouse model using intranasal transfer of BMDCs was used.
Results: Challenge of moDCs with L. lactis G121 induced release of IL-12p70, IL-23, IL-10 and IFN-β. The inhibitors Cytochalasin D and Bafilomycin A1 (Baf) drastically inhibited cytokine production, indicating the importance of bacteria uptake and endosomal acidification. Baf-treatment of moDCs also inhibited L. lactis G121-induced up-regulation of co-stimulatory molecules and thus L. lactis G121-induced IFN-γ and IL-10 release in co-culture with T-cells. Using an OVA mouse model with intranasal transfer of differently treated BMDCs, we demonstrated the importance of endosomal acidification in L. lactis G121-mediated allergy protection also in vivo. Activation of BMDCs from TLR13-deficient mice strongly implicates TLR13 as a major host sensor of L. lactis G121.
Conclusion: L. lactis G121 uptake, endosomal acidification and activation of TLR13 underlie the allergy-protective effect of the cowshed bacterium. Whether the TLR13 activating or other L. lactis G121 molecular patterns are similarly operative in humans is a question arising.