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Transcriptome analysis of virus-specific H2-Db-GP33-41+CD8+ T cells from WT or PSGL-1 KO mouse spleens at day 9 post LCMV Cl 13 infection

ABSTRACT: Chronic viruses and cancers thwart immune responses in humans by inducing T cell dysfunction. Using a murine chronic virus that models human infections, we investigated the function of the adhesion molecule, P-selectin glycoprotein ligand-1 (PSGL-1) that is upregulated on responding T cells. PSGL-1-deficient mice unexpectedly cleared the virus due to dramatic increases in the intrinsic survival of multifunctional effector T cells that had downregulated PD-1 and other inhibitory receptors. Notably, this response resulted in CD4+ T cell-dependent immunopathology. Mechanistically, PSGL-1 ligation on exhausted CD8+ T cells inhibited TCR and IL-2 signaling, and upregulated PD-1, leading to diminished survival with TCR stimulation. In models of malignant melanoma where T cell dysfunction occurs, PSGL-1-deficiency led to PD-1 downregulation, improved T cell responses, and tumor control. Thus, PSGL-1 plays a fundamental role in balancing viral control and immunopathology, and also functions as a checkpoint that regulates T cell responses in the tumor microenvironment.

ORGANISM(S): Mus musculus

PROVIDER: GSE80113 | GEO | 2016/06/30

SECONDARY ACCESSION(S): PRJNA317960

REPOSITORIES: GEO

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Transcriptome analysis of virus-specific H2-Db-GP33-41+CD8+ T cells from WT or PSGL-1 KO mouse spleens at day 9 post LCMV Cl 13 infection

Project description:Chronic viruses and cancers thwart immune responses in humans by inducing T cell dysfunction. Using a murine chronic virus that models human infections, we investigated the function of the adhesion molecule, P-selectin glycoprotein ligand-1 (PSGL-1) that is upregulated on responding T cells. PSGL-1-deficient mice unexpectedly cleared the virus due to dramatic increases in the intrinsic survival of multifunctional effector T cells that had downregulated PD-1 and other inhibitory receptors. Notably, this response resulted in CD4+ T cell-dependent immunopathology. Mechanistically, PSGL-1 ligation on exhausted CD8+ T cells inhibited TCR and IL-2 signaling, and upregulated PD-1, leading to diminished survival with TCR stimulation. In models of malignant melanoma where T cell dysfunction occurs, PSGL-1-deficiency led to PD-1 downregulation, improved T cell responses, and tumor control. Thus, PSGL-1 plays a fundamental role in balancing viral control and immunopathology, and also functions as a checkpoint that regulates T cell responses in the tumor microenvironment. WT or PSGL-1 KO mice were infected with 2 x 10^6 PFU LCMV Clone 13. Spleens from 10 WT or 10 PSGL-1 KO animals were pooled and processed. CD8+ T cells were negatively enriched from WT or PSGL-1 KO spleens (EasySep Stemcell). Purified T cells were stained with propidium iodide (PI) for 10 minutes on ice, cells were washed. CD8+ T cells were stained with H2-Db-GP33-41 tetramers (NIH) and FACS sorted (BD FACS Aria). Sorted tetramer+ cells were PI negative and purity was >98%. Experiment was repeated twice to generate 2 WT (WT 1; WT 2) and 2 PSGL-1 KO (KO 1; KO 2) samples that represented 10 pooled spleens per sample.

2016-06-30 | E-GEOD-80113 | biostudies-arrayexpress

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Project description:We use scRNA-seq to show the differences in tumor-infiltrating immune cells among IgG, anti-PD-1, anti-PSGL-1, and combination anti-PD-1 and anti-PSGL-1 treated mice. We show that anti-PSGL-1 treatment resulted in an increase in neutrophil and T cells, anti-PD-1 treatment resulted in an increase in macrophages, and the combination resulted in an increase in T cells and macrophages when compared to the tumors of IgG treated mice. Additionally, we show that Tregulatory cells are decreased in the tumors of anti-PSGL-1 and combination treated mice. Further, we find that anti-PSGL-1 treated CD8 T cells show upregulation of activation and survival genes, while combination treatment increased effector gene expression in CD8 T cells. Both anti-PSGL-1 treatment and combination treatment increase effector gene expression in CD4 T cells when compared to IgG. This scRNA-seq study shows the impact of IgG, anti-PD-1, anti-PSGL-1, and combination anti-PSGL-1 and anti-PD-1 antibody tteatment on tumor-infiltrating immune cells in B16-GP33 melnoma tumor bearing mice.

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scRNA-seq comparison of B16-GP33 tumor-infiltrating immune cells from IgG, anti-PD-1, anti-PSGL-1, or combination anti-PD-1 and anti-PSGL-1 treated mice

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