Salmonella effector SseL induces PD-L1 up-regulation and T cell inactivation via beta-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 causing culling of the activated T-cell; however, the underlying mechanism behind this upregulation is not known. Our findings indicate that the upregulation of PD-L1 is through Salmonella pathogenicity island 2 (SPI-2) encoded effectors since PFA-fixed STM WT and STM{Delta}ssaV (which is unable to secrete effector proteins) did not alter PD-L1 levels. We have further investigated the role of the SPI-2 effector SseL (a deubiquitinase known to affect the NF-B pathway) in PD-L1 upregulation. Our study identifies SPI-2 effector SseL to be crucial for upregulating PD-L1 in vitro as well as in vivo murine models. The increase in PD-L1 levels induced by STM WT facilitates colonization in secondary infection sites in C57BL/6 mice, including the liver and spleen, while the STM{Delta}sseL strain exhibits significant colonization defects. Notably, despite the reduced colonization capacity of STM{Delta}sseL, infected mice exhibit earlier mortality associated with heightened inflammation. We further elucidated the molecular mechanism behind PD-L1 upregulation and observed that bacterial effector SseL helps in the stabilization of {beta}-catenin inside the cell. {beta}-catenin thus translocates into the nucleus and directly regulates the transcriptional levels of PD-L1, which is abrogated upon using {beta}-catenin/TCF inhibitor FH535. Collectively, our study elucidates the mechanism by which Salmonella mediates immune suppression through PD-L1 upregulation. O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/620790v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@12ba486org.highwire.dtl.DTLVardef@3e8b40org.highwire.dtl.DTLVardef@28546corg.highwire.dtl.DTLVardef@1bea897_HPS_FORMAT_FIGEXP M_FIG Abstract figure: Schematic representation of SseL mediated PDL1 upregulation and further affecting the T cell proliferation C_FIG