PSGL-1 Is a T Cell Intrinsic Inhibitor That Regulates Effector and Memory Differentiation and Responses During Viral Infection

Tinoco, Roberto; Neubert, Emily N.; Stairiker, Christopher J.; Henriquez, Monique L.; Bradley, Linda M.

doi:10.3389/fimmu.2021.677824

Cited by 15 publications

(13 citation statements)

References 32 publications

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“…Since Selplg -/- P14 + T cells drastically declined during Cl13 infection compared to WT T cells and we observed no differences between their proliferation suggests that Selplg -/- P14 + T cells had a decreased ability to survive, which could also be explained by their diminished Tpex population. This contrasts with what was observed in Selplg -/- mice infected with Arm or Cl13 where T cell survival was increased, in part due to the viral clearance that occurs in Selplg -/- infected mice ( 8 , 38 ). The importance of immune checkpoints in T cell differentiation was also highlighted in studies using WT and Selplg -/- SMARTA + and P14 + T cells transferred in WT Arm infected mice, which showed that even though more memory Selplg -/- TCR transgenic T cells developed, they failed to be recalled during a secondary infection ( 38 ).…”

Section: Discussioncontrasting

confidence: 82%

“…This contrasts with what was observed in Selplg -/- mice infected with Arm or Cl13 where T cell survival was increased, in part due to the viral clearance that occurs in Selplg -/- infected mice ( 8 , 38 ). The importance of immune checkpoints in T cell differentiation was also highlighted in studies using WT and Selplg -/- SMARTA + and P14 + T cells transferred in WT Arm infected mice, which showed that even though more memory Selplg -/- TCR transgenic T cells developed, they failed to be recalled during a secondary infection ( 38 ). A similar phenotype in defective memory differentiation was also observed in PD-1-deficient T cells responding to respiratory viral infection ( 43 ).…”

Section: Discussioncontrasting

confidence: 82%

“…Selplg -/- mice were also shown to have increased anti-tumor immunity to melanoma ( 8 ). Additionally, during acute viral infection, Selplg -/- T cells were increased at both the effector and memory stage ( 38 ). However, the cell-intrinsic PSGL-1 function in the differentiation of exhausted CD4 + and CD8 + T cells and its role during the reinvigoration process after ICI therapy is unknown.…”

Section: Introductionmentioning

confidence: 99%

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PD-1 Immune Checkpoint Blockade and PSGL-1 Inhibition Synergize to Reinvigorate Exhausted T Cells

et al. 2022

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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 (Selplg) 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 Selplg-/- T cells had increased expansion in melanoma tumors and in early stages of chronic viral infection. Despite their increase, both WT and Selplg-/- T cells eventually became phenotypically and functionally exhausted. Even though virus-specific Selplg-/- CD4+ and CD8+ 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 Selplg-/- CD8+ Tpex (SLAMF6hiTIM3lo, PD-1+TIM3+, TOX+, TCF-1+) cell frequencies and numbers were decreased compared to WT T cells. Importantly, even though virus-specific Selplg-/- CD4+ and CD8+ T cells were lower, they were reinvigorated more effectively than WT T cells after anti-PD-L1 treatment. We found increased SELPLG expression in Hepatitis C-specific CD8+ 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+ and CD8+ 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.

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Section: Discussioncontrasting

confidence: 82%

Section: Discussioncontrasting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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PD-1 Immune Checkpoint Blockade and PSGL-1 Inhibition Synergize to Reinvigorate Exhausted T Cells

et al. 2022

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“…Regarding the adaptive immune system, we found a high proportion of effector memory and terminally differentiated subpopulations, decreased CD226 expression and high CD162 expression in CD4 + T cells in severe patients. The CD162 (PSGL-1) has been described by having a role in inducing T cell exhaustion and driving effector and memory in T cells during acute infection [ 36 , 37 , 38 ]. The involvement of this receptor in the changes of T cell memory profile and the effect of its blockade in T cell function of COVID-19 patients should be further studied.…”

Section: Discussionmentioning

confidence: 99%

Differential Immune Checkpoint and Ig-like V-Type Receptor Profiles in COVID-19: Associations with Severity and Treatment

Lozano-Rodríguez

Terrón-Arcos

Lopez³

et al. 2022

JCM

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Identifying patients’ immune system status has become critical to managing SARS-CoV-2 infection and avoiding the appearance of secondary infections during a hospital stay. Despite the high volume of research, robust severity and outcome markers are still lacking in COVID-19. We recruited 87 COVID-19 patients and analyzed, by unbiased automated software, 356 parameters at baseline emergency department admission including: high depth immune phenotyping and immune checkpoint expression by spectral flow cytometry, cytokines and other soluble molecules in plasma as well as routine clinical variables. We identified 69 baseline alterations in the expression of immune checkpoints, Ig-like V type receptors and other immune population markers associated with severity (O2 requirement). Thirty-four changes in these markers/populations were associated with secondary infection appearance. In addition, through a longitudinal sample collection, we described the changes which take place in the immune system of COVID-19 patients during secondary infections and in response to corticosteroid treatment. Our study provides information about immune checkpoint molecules and other less-studied receptors with Ig-like V-type domains such as CD108, CD226, HVEM (CD270), B7H3 (CD276), B7H5 (VISTA) and GITR (CD357), defining these as novel interesting molecules in severe and corticosteroids-treated acute infections.

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“…Compared to healthy control participants, histopathological confirmation revealed an increase in parenchymal CD163 + microglia/ macrophages paralleled by increased expression of PSGL-1. Despite being considered a T cell immune checkpoint [ 41 , 42 ], PSGL-1 has been shown to aid in the spreading and metastasis of melanoma and colon cancer cells via P-selectin (SELP) mediated platelet activation [ 43 , 44 ]. In glioblastoma, cancer cells overexpress and oversecrete SELP to exploit PSGL-1 signaling in glioma-associated microglia/macrophages.…”

Section: Discussionmentioning

confidence: 99%

Immunophenotyping of Circulating and Intratumoral Myeloid and T Cells in Glioblastoma Patients

Marx

Wilken

Miebach

et al. 2022

Cancers

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Glioblastoma is the most common and lethal primary brain malignancy that almost inevitably recurs as therapy-refractory cancer. While the success of immune checkpoint blockade (ICB) revealed the immense potential of immune-targeted therapies in several types of cancers outside the central nervous system, it failed to show objective responses in glioblastoma patients as of now. The ability of glioblastoma cells to drive multiple modes of T cell dysfunction while exhibiting low-quality neoepitopes, low-mutational load, and poor antigen priming limits anti-tumor immunity and efficacy of antigen-unspecific immunotherapies such as ICB. An in-depth understanding of the GBM immune landscape is essential to delineate and reprogram such immunosuppressive circuits during disease progression. In this view, the present study aimed to characterize the peripheral and intratumoral immune compartments of 35 glioblastoma patients compared to age- and sex-matched healthy control probands, particularly focusing on exhaustion signatures on myeloid and T cell subsets. Compared to healthy control participants, different immune signatures were already found in the peripheral circulation, partially related to the steroid medication the patients received. Intratumoral CD4+ and CD8+ TEM cells (CD62Llow/CD45ROhigh) revealed a high expression of PD1, which was also increased on intratumoral, pro-tumorigenic macrophages/microglia. Histopathological analysis further identified high PSGL-1 expression levels of the latter, which has recently been linked to increased metastasis in melanoma and colon cancer via P-selectin-mediated platelet activation. Overall, the present study comprises immunophenotyping of a patient cohort to give implications for eligible immunotherapeutic targets in neurooncology in the future.

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PSGL-1 Is a T Cell Intrinsic Inhibitor That Regulates Effector and Memory Differentiation and Responses During Viral Infection

Cited by 15 publications

References 32 publications

PD-1 Immune Checkpoint Blockade and PSGL-1 Inhibition Synergize to Reinvigorate Exhausted T Cells

PD-1 Immune Checkpoint Blockade and PSGL-1 Inhibition Synergize to Reinvigorate Exhausted T Cells

Differential Immune Checkpoint and Ig-like V-Type Receptor Profiles in COVID-19: Associations with Severity and Treatment

Immunophenotyping of Circulating and Intratumoral Myeloid and T Cells in Glioblastoma Patients

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