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Immunol."],"abstract":"<jats:p>Chronic viral infections where the antigen persists long-term, induces an exhaustion phenotype in responding T cells. It is now evident that immune checkpoints on T cells including PD-1, CTLA-4, and PSGL-1 (<jats:italic>Selplg<\/jats:italic>) are linked with the differentiation of exhausted cells. Chronic T cell receptor signaling induces transcriptional signatures that result in the development of various exhausted T cell subsets, including the stem-like T cell precursor exhausted (Tpex) cells, which can be reinvigorated by immune checkpoint inhibitors (ICIs). While PSGL-1 has been shown to inhibit T cell responses in various disease models, the cell-intrinsic function of PSGL-1 in the differentiation, maintenance, and reinvigoration of exhausted T cells is unknown. We found <jats:italic>Selplg<jats:sup>-\/-<\/jats:sup><\/jats:italic> T cells had increased expansion in melanoma tumors and in early stages of chronic viral infection. Despite their increase, both WT and <jats:italic>Selplg<jats:sup>-\/-<\/jats:sup><\/jats:italic> T cells eventually became phenotypically and functionally exhausted. Even though virus-specific <jats:italic>Selplg<jats:sup>-\/-<\/jats:sup><\/jats:italic> CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T cells were increased at the peak of T cell expansion, they decreased to lower levels than WT T cells at later stages of chronic infection. We found that <jats:italic>Selplg<jats:sup>-\/-<\/jats:sup><\/jats:italic> CD8<jats:sup>+<\/jats:sup> Tpex (SLAMF6<jats:sup>hi<\/jats:sup>TIM3<jats:sup>lo<\/jats:sup>, PD-1<jats:sup>+<\/jats:sup>TIM3<jats:sup>+<\/jats:sup>, TOX<jats:sup>+<\/jats:sup>, TCF-1<jats:sup>+<\/jats:sup>) cell frequencies and numbers were decreased compared to WT T cells. Importantly, even though virus-specific <jats:italic>Selplg<jats:sup>-\/-<\/jats:sup><\/jats:italic> CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T cells were lower, they were reinvigorated more effectively than WT T cells after anti-PD-L1 treatment. We found increased <jats:italic>SELPLG<\/jats:italic> expression in Hepatitis C-specific CD8<jats:sup>+<\/jats:sup> T cells in patients with chronic infection, whereas these levels were decreased in patients that resolved the infection. Together, our findings showed multiple PSGL-1 regulatory functions in exhausted T cells. We found that PSGL-1 is a cell-intrinsic inhibitor that limits T cells in tumors and in persistently infected hosts. Additionally, while PSGL-1 is linked with T cell exhaustion, its expression was required for their long-term maintenance and optimal differentiation into Tpex cells. Finally, PSGL-1 restrained the reinvigoration potential of exhausted CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T cells during ICI therapy. Our findings highlight that targeting PSGL-1 may have therapeutic potential alone or in combination with other ICIs to reinvigorate exhausted T cells in patients with chronic infections or cancer.<\/jats:p>","DOI":"10.3389\/fimmu.2022.869768","type":"journal-article","created":{"date-parts":[[2022,6,14]],"date-time":"2022-06-14T05:28:57Z","timestamp":1655184537000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":28,"title":["PD-1 Immune Checkpoint Blockade and PSGL-1 Inhibition Synergize to Reinvigorate Exhausted T Cells"],"prefix":"10.3389","volume":"13","author":[{"given":"Karla M.","family":"Viramontes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily N.","family":"Neubert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia 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