PD-1 Expression in Acute Hepatitis C Virus (HCV) Infection Is Associated with HCV-Specific CD8 Exhaustion

Urbani, Simona; Amadei, Barbara; Tola, D.; Massari, Marco; Schivazappa, Simona; Missale, Gabriele; Ferrari, Carlo

doi:10.1128/jvi.01177-06

Cited by 515 publications

(492 citation statements)

References 17 publications

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“…1,12,14,15 In some of them, PDCD1 downregulation of immune reactions is defective, as in autoimmunity and, possibly, in atherosclerosis, 13 whereas in others it is inappropriately strong, as in chronic viral infections. The hypothesis of an enhancer in the 4th intron of the gene that bears a regulatory polymorphism deserves, therefore, to be tested.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of the functional relevance of a putative regulatory SNP of PDCD1, PD1.3, associated with systemic lupus erythematosus

et al. 2008

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This study aimed to test the functional effects of the PD1.3 single nucleotide polymorphism (SNP) (rs11568821), which were proposed based on its association to systemic lupus erythematosus (SLE) susceptibility and in electrophoretic mobility shift assays (EMSA) results. We analysed transcriptional effects of the PD1.3 locus by enhancer reporter assays. Results were against the hypothesis that the PD1.3 locus acts as enhancer in transcriptional regulation of PDCD1. In addition, they excluded a differential effect of the PD1.3 alleles. EMSA results confirmed that oligonucleotides with the PD1.3 G allele bind RUNX1 but not those with the A allele. However, binding to PD1.3 G oligonucleotides was much lower than binding to positive control oligonucleotides. Criss-cross experiments showed that this was due to flanking nucleotides in the PD1.3 sequence that negatively affect RUNX1 binding. These results cast doubts on the functional relevance of the PD1.3 SNP and, together with the lack of association in several studies, put into question its role as an SLE susceptibility factor. Investigation of other PDCD1 polymorphisms is needed to uncover the possible effect of this gene on SLE susceptibility.

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Section: Discussionmentioning

confidence: 99%

“…13 The involvement of PDCD1 in chronic viral infections has already been confirmed in human diseases of great impact such as AIDS 14 and chronic viral hepatitis. 15 Therefore, if genetic variation of PDCD1 is associated with changes in PDCD1 function, it could have repercussions in human health well beyond SLE.…”

Section: Introductionmentioning

confidence: 99%

Analysis of the functional relevance of a putative regulatory SNP of PDCD1, PD1.3, associated with systemic lupus erythematosus

et al. 2008

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“…5 Increasing evidence demonstrates that upregulation of the PD-1 inhibitory receptor mediates HIV-specific CD8 1 T-cell functional exhaustion and CD8 1 T cell is apoptosis-sensitive, resulting in an impairment of CD8 1 T cell's ability to control virus replication. [6][7][8][9] Involvement of the PD-1 pathway has also been shown during hepatitis B and C virus infection [10][11][12][13] with PD-L1 expression demonstrated in situ on a wide variety of solid tumors including pancreas, lung, ovarian and bladder tumors. [14][15][16][17][18] Studies relating PD-L1 expression on tumors to disease outcome show that PD-L1 expression strongly correlates with unfavorable prognosis in kidney, bladder, gastric and pancreatic cancer.…”

Section: Introductionmentioning

confidence: 96%

Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer

et al. 2010

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T-cell tolerance is an important mechanism for tumor escape, but the molecular pathways involved in T-cell tolerance remain poorly understood. It remains unknown whether the inhibitory immunoreceptor programmed death-1 (PD-1) plays a role in conditions of human non-small cell lung cancer (NSCLC). In this study, we detected PD-1 expression on CD8 1 T cells from healthy control peripheral blood mononuclear cells (PBMCs) and the PBMCs of NSCLC patients as well as NSCLC tissues. Results showed that tumor-infiltrating CD8 1 T cells had increased PD-1 expression and impaired immune function, including reducing cytokine production capability and impairing capacity to proliferate. Blockade of the PD-1/PD-L1 pathway by the PD-L1-specific antibody partially restored cytokine production and cell proliferation. These data provide direct evidence that the PD-1/PD-L1 pathway is involved in CD8 1 T-cell dysfunction in NSCLC patients. Moreover, blocking this pathway provides a potential therapy target in lung cancer.

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“…7,8 PD-1 is a significant marker for T lymphocytes malfunctioning in response to viral infection. [9][10][11][12] Recently, elevated PD-1 expression in intratumoral lymphocytes and its association with the functional impairment of TILs have also been reported in melanoma, hepatocellular carcinoma, and Hodgkin lymphoma. [13][14][15] However, reports on the prognostic value of PD-1 expression for cancer therapy, analyzed in only a few studies, are inconsistent.…”

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confidence: 98%

Increase of programmed death-1-expressing intratumoral CD8 T cells predicts a poor prognosis for nasopharyngeal carcinoma

et al. 2010

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Intratumoral cytotoxic T lymphocytes are critical for controlling tumor recurrence, and programmed death-1 (PD-1) is a recognized marker of T-cell dysfunction. We analyzed this marker and its binding ligands in nasopharyngeal tumor tissue and non-cancerous nasopharyngeal control tissue to retrospectively evaluate the correlation between its expression and the post-treatment outcome of nasopharyngeal carcinoma patients. Using double immunofluorescence staining, we found that the expression of PD-1 in CD8 T cells in tumor tissue was significantly higher than in control tissue (mean: 28.4 vs 3.9%, Po0.0001). Although the expression rate of PD-1 in intratumoral CD8 cells was not associated with the other clinicopathological parameters examined, the higher expression rate in this subset of T cells significantly correlated with a poorer prognosis of overall survival, disease-free survival, and locoregional recurrence-free survival of the cancer patients (P ¼ 0.05, 0.007, and 0.004, respectively). Multivariate analysis confirmed it as an independent risk factor for death, treatment failure, and local recurrence of nasopharyngeal carcinoma. On the other hand, the expression of PD-1 in CD4 T cells and of its ligands in epithelial and stromal cells was not significantly different between tumor and control tissue, and its expression was not associated with clinical outcome of the cancer patients. We propose that PD-1 expression in CD8 cells reflects the selective suppression of cytotoxic lymphocytes in the tumor microenvironment and predicts recurrence of nasopharyngeal carcinoma after conventional therapies.

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PD-1 Expression in Acute Hepatitis C Virus (HCV) Infection Is Associated with HCV-Specific CD8 Exhaustion

Cited by 515 publications

References 17 publications

Analysis of the functional relevance of a putative regulatory SNP of PDCD1, PD1.3, associated with systemic lupus erythematosus

Analysis of the functional relevance of a putative regulatory SNP of PDCD1, PD1.3, associated with systemic lupus erythematosus

Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer

Increase of programmed death-1-expressing intratumoral CD8 T cells predicts a poor prognosis for nasopharyngeal carcinoma

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