Salmonella effector SseL induces PD-L1 up-regulation and T cell inactivation via β-catenin signalling axis

Abstract The upregulation of 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 PFA-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.