Salmonella Effector SseL Induces Programmed Death Ligand 1 Upregulation and T-Cell Inactivation via the β-Catenin Signaling Axis.

Abstract

The upregulation of programmed death ligand 1 (PD-L1) by various pathogens is a recognized strategy to evade the adaptive immune response. Salmonella infection also upregulates PD-L1 levels; however, the underlying mechanism remains unclear. Our study reveals that this upregulation is mediated by Salmonella pathogenicity island 2 (SPI-2) effectors, as paraformaldehyde fixed and STMΔssaV fail to alter PD-L1 levels. We have further investigated the role of the SPI-2 effector SseL (a deubiquitinase) in PD-L1 upregulation, and our study reveals SseL to be crucial for upregulating PD-L1 in vitro as well as in vivo murine models. STMΔsseL exhibits colonization defects in secondary infection sites such as the liver and spleen. Notably, STMΔsseL infected mice show earlier mortality associated with heightened inflammation. Mechanistically, SseL stabilizes β-catenin, which translocates to the nucleus and leads to PD-L1 transcription, which is abrogated by the β-catenin/TCF inhibitor FH535. Collectively, our study elucidates the mechanism by which Salmonella mediates immune suppression through PD-L1 upregulation.