Speaker
Description
Cutaneous infections are controlled by the skin immune system eliciting innate as well as adaptive anti-microbial immune responses. Different studies, including our work, revealed that critical involvement of the tumor necrosis factor (TNF)/TNF receptor superfamily are regulating the cutaneous immunity. However, to complete their life cycle, pathogenic microorganisms need to suppress host anti-microbial immune responses. In particular CD4+Foxp3+ regulatory T cells (Treg) and MDSCs play a crucial role in the inhibition of cellular immunity. The molecular mechanisms determining the activation, expansion or migratory behaviour of Treg and MDSCs during cutaneous infections are still poorly understood. Upon intradermal infection with S. aureus in the back skin, K14-RANKL tg mice exhibited an increased skin lesion size as well as bacterial load compared to WT controls. This effect was mediated by increased abundance of Treg in K14-RANKL tg mice. To address the in-vivo relevance of Treg for the suppression of anti-bacterial immunity in S. aureus, K14-RANKL tg mice were bred with DEREG mutants, expressing the diphtheria toxin receptor (DTR) under control of the Foxp3 promoter. Subsequently, Treg were depleted in K14-RANKL tg x DEREG double mutants by intraperitoneal injection of diphtheria toxin (DT) before and after S. aureus infection. This results in the accumulation of G-MDSCs (granulocytic Ly6Ghigh Ly6Clow) and downregulation of M-MDSC (monocytic Ly6C+). Together, this data indicates that RANK-RANKL signaling increases Treg frequencies that lead to suppression of host anti-microbial immune responses while Treg deficiency results in an increase of G-MDSCs and the suppression of M-MDSC populations.
