Abstract
The inhibitory receptor PD-1 is expressed on T cells to inhibit select functions when ligated. The complete signaling mechanism downstream of PD-1 has yet to be uncovered. Here, we discovered phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG) is phosphorylated following PD-1 ligation and associate this with inhibitory T cell function. Clinical cohort analysis correlates low PAG expression with increased survival from numerous tumor types. PAG knockdown in T cells prevents PD-1-mediated inhibition of cytokine secretion, cell adhesion, CD69 expression, and ERK204/187 phosphorylation, and enhances phosphorylation of SRC527 following PD-1 ligation. PAG overexpression rescues these effects. In vivo, PAG contributes greatly to the growth of two murine tumors, MC38 and B16, and limits T cell presence within the tumor. Moreover, PAG deletion sensitizes tumors to PD-1 blockade. Here PAG is established as a critical mediator of PD-1 signaling and as a potential target to enhance T cell activation in tumors.
Highlights
The inhibitory receptor PD-1 is expressed on T cells to inhibit select functions when ligated
We have found that three tyrosines in the cytoplasmic tail of phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG) are phosphorylated following PD-1 ligation, which led us to the hypothesis that PAG is an effector downstream of PD-1 that contributes to the inhibitory function of PD-1 in T cells
We found 49 proteins with phosphotyrosines that were more prevalent in T cells stimulated with anti-CD3 and PDL2 in combination, and 22 of these 49 proteins are plasma membrane associated (Fig. 1a and Table 1)
Summary
The inhibitory receptor PD-1 is expressed on T cells to inhibit select functions when ligated. Surface expression of the inhibitory receptor PD-1 is upregulated on activated T cells[1], allowing for enhanced signaling in response to its ligands PD-L1 or PD-L2 being expressed on other cells within the tumor microenvironment, and increased inhibition of numerous T cells functions. For these reasons, immune checkpoint inhibitors, including PD-1-targeting antibodies, are proving successful in the treatment of diverse tumors. We generated PAG-deficient and PAG-overexpressing T cells, and utilized PAG knockout mice to interrogate the contributions of PAG to PD-1-driven T cell inhibition
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
