B. burgdorferi sensu lato-induced inhibition of antigen presentation is mediated by RIP1 signaling resulting in impaired functional T cell responses towards Candida albicans

Abstract

Antigen presentation is a crucial innate immune cell function that instructs adaptive immune cells. Loss of this pathway severely impairs the development of adaptive immune responses. To investigate whether B. burgdorferi sensu lato. spirochetes modulate the induction of an effective immune response, primary human PBMCs were isolated from healthy volunteers and stimulated with B. burgdorferi s.l. Through cell entry, TNF receptor I, and RIP1 signaling cascades, B. burgdorferi s.l. strongly downregulated genes and proteins involved in antigen presentation, specifically HLA-DM, MHC class II and CD74. Antigen presentation proteins were distinctively inhibited in monocyte subsets, monocyte-derived macrophages, and dendritic cells. When compared to a range of other pathogens, B. burgdorferi s.l.-induced suppression of antigen presentation appears to be specific. Inhibition of antigen presentation interfered with T-cell recognition of B. burgdorferi s.l., and memory T-cell responses against Candidaalbicans. Re-stimulation of PBMCs with the commensal microbe C.albicans following B. burgdorferi s.l. exposure resulted in significantly reduced IFN-γ, IL-17 and IL-22 production. These findings may explain why patients with Lyme borreliosis develop delayed adaptive immune responses. Unravelling the mechanism of B. burgdorferi s.l.-induced inhibition of antigen presentation, via cell entry, TNF receptor I, and RIP1 signaling cascades, explains the difficulty to diagnose the disease based on serology and to obtain an effective vaccine against Lyme borreliosis.