scholarly journals Revisiting the PD-1 pathway

2020 ◽  
Vol 6 (38) ◽  
pp. eabd2712 ◽  
Author(s):  
Nikolaos Patsoukis ◽  
Qi Wang ◽  
Laura Strauss ◽  
Vassiliki A. Boussiotis
Keyword(s):  
T Cells ◽  
Molecular Targets ◽  
Peripheral Tolerance ◽  
Inhibitory Receptor ◽  
Activated T Cells ◽  
Therapeutic Success ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
And Function ◽  
Blocking Antibodies

Programmed Death-1 (PD-1; CD279) is an inhibitory receptor induced in activated T cells. PD-1 engagement by its ligands, PD-L1 and PD-L2, maintains peripheral tolerance but also compromises anti-tumor immunity. Blocking antibodies against PD-1 or its ligands have revolutionized cancer immunotherapy. However, only a fraction of patients develop durable antitumor responses. Clinical outcomes have reached a plateau without substantial advances by combinatorial approaches. Thus, great interest has recently emerged to investigate, in depth, the mechanisms by which the PD-1 pathway transmits inhibitory signals with the goal to identify molecular targets for improvement of the therapeutic success. These efforts have revealed unpredictable dimensions of the pathway and uncovered novel mechanisms involved in PD-1 and PD-L1 regulation and function. Here, we provide an overview of the recent advances on the mechanistic aspects of the PD-1 pathway and discuss the implications of these new discoveries and the gaps that remain to be filled.

scholarly journals The Programmed Death-1 (PD-1) Pathway Regulates Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice

2003 ◽  
Vol 198 (1) ◽  
pp. 63-69 ◽  
Author(s):  
Mohammed Javeed I. Ansari ◽  
Alan D. Salama ◽  
Tanuja Chitnis ◽  
R. Neal Smith ◽  
Hideo Yagita ◽  
...  
Keyword(s):  
Cytotoxic T Lymphocyte ◽  
Autoimmune Diabetes ◽  
Costimulatory Molecule ◽  
Nod Mice ◽  
Interferon Γ ◽  
Peripheral Tolerance ◽  
Activated T Cells ◽  
Nonobese Diabetic ◽  
Programmed Death ◽  
Programmed Death 1

Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1–PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon γ–producing GAD-reactive splenocytes was increased after PD-1–PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1–PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.

scholarly journals Critical Role of the Programmed Death-1 (PD-1) Pathway in Regulation of Experimental Autoimmune Encephalomyelitis

2003 ◽  
Vol 198 (1) ◽  
pp. 71-78 ◽  
Author(s):  
Alan D. Salama ◽  
Tanuja Chitnis ◽  
Jaime Imitola ◽  
Mohammed Javeed I. Ansari ◽  
Hisaya Akiba ◽  
...  
Keyword(s):  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Critical Role ◽  
Peripheral Tolerance ◽  
Delayed Type Hypersensitivity ◽  
Autoimmune Encephalomyelitis ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Deficient Mice ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is mediated by autoantigen-specific T cells dependent on critical costimulatory signals for their full activation and regulation. We report that the programmed death-1 (PD-1) costimulatory pathway plays a critical role in regulating peripheral tolerance in murine EAE and appears to be a major contributor to the resistance of disease induction in CD28-deficient mice. After immunization with myelin oligodendrocyte glycoprotein (MOG) there was a progressive increase in expression of PD-1 and its ligand PD-L1 but not PD-L2 within the central nervous system (CNS) of mice with EAE, peaking after 3 wk. In both wild-type (WT) and CD28-deficient mice, PD-1 blockade resulted in accelerated and more severe disease with increased CNS lymphocyte infiltration. Worsening of disease after PD-1 blockade was associated with a heightened autoimmune response to MOG, manifested by increased frequency of interferon γ–producing T cells, increased delayed-type hypersensitivity responses, and higher serum levels of anti-MOG antibody. In vivo blockade of PD-1 resulted in increased antigen-specific T cell expansion, activation, and cytokine production. Interestingly, PD-L2 but not PD-L1 blockade in WT animals also resulted in disease augmentation. Our data are the first demonstration that the PD-1 pathway plays a critical role in regulating EAE.

scholarly journals Suppressed Programmed Death 1 Expression on CD4+ and CD8+ T Cells in Psoriatic Patients

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Joanna Bartosińska ◽  
Ewelina Zakrzewska ◽  
Dorota Raczkiewicz ◽  
Joanna Purkot ◽  
Anna Michalak-Stoma ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Chronic Inflammatory Disease ◽  
Peripheral Tolerance ◽  
Control Group ◽  
Cell Immunity ◽  
Programmed Death ◽  
Peripheral T Cells ◽  
Programmed Death 1 ◽  
The Absolute

Psoriasis is a chronic inflammatory disease mediated by T cell immunity. Programmed death 1 (PD-1), a coinhibitory receptor, plays an important role in immune regulation and maintaining peripheral tolerance. The aim of the study was to compare the expression of PD-1 on the peripheral T cells between psoriatic patients and healthy controls. The study included 75 psoriatic patients and 52 healthy volunteers. The percentages and absolute numbers of CD3+, CD4+, CD8+, CD4+PD-1+, and CD8+PD-1+ T cells were analyzed using flow cytometry. The absolute numbers and percentages of CD4+PD-1+ and CD8+PD-1+ T cells were significantly decreased in the psoriatic patients in comparison with the control group. No significant correlations were found between the absolute numbers and percentages of CD4+PD-1+ or CD8+PD-1+ T cells and clinical characteristics of psoriasis. Decreased PD-1 expression on the T cells may be responsible for impaired negative regulation of immune response in psoriasis pathogenesis.

The Systemic Activation of Programmed Death 1-PD-L1 Axis Protects Systemic Lupus Erythematosus Model from Nephritis

2017 ◽  
Vol 46 (5) ◽  
pp. 371-379 ◽  
Author(s):  
Wenjun Liao ◽  
Hua Zheng ◽  
Sha Wu ◽  
Yanmei Zhang ◽  
Wei Wang ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
B Cells ◽  
Lupus Erythematosus ◽  
Enzyme Linked Immunosorbent Assay ◽  
Systemic Lupus ◽  
Activated T Cells ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Ifn Γ

Background: Systemic lupus erythematosus (SLE) is characterized by abnormal activated T cells, autoreactive B cells, and massive cytokines. The CD4+ T cells determined B-cells differentiation and cytokines production. The programmed death 1 (PD-1) is the checkpoint immunoinhibitory receptor of activated T cells, and its engagement could exhaust T cells. In this study, we investigated the role of PD-1 systemic engagement with PD-L1-Ig in lupus-like nephritis in SLE mice. Methods: The murine PD-L1-Ig was injected into SLE-prone mice. The proteinuria and survival ratio were monitored. The production of anti-dsDNA autoantibodies and cytokines in serum were measured by enzyme-linked immunosorbent assay. The cytokine-producing T cells (interferon-γ, IFN-γ and IL-17α) in kidney and spleen were detected with flowcytometry. The pathological evaluation of the Ig deposition in the glomeruliand was determined with immunofluorescence. Lymphocytes in 24-h urine were detected with flowcytometry. Results: The systemic administration of PD-L1-Ig activated PD-1-PD-L1 axis of CD4+ T lymphocytes, suppressed Th17 formation in many organs, including the spleen and the kidney, demolished abnormal production of cytokines (IFN-γ, IL-17, and IL-10) and anti-dsDNA autoantibodies in serum, inhibited immunoglobulin G deposition in the glomeruli with the decrease of proteinuria, and activated T cells in urine. Accordingly, the systemic conjugation of PD-L1-PD-1 impaired renal autoimmune injure and prolonged survival time. Conclusion: Our research demonstrated that the protective function of systemic activation of PD-1-PD-L1 axis with PD-L1-Ig attenuates the nephritis in SLE-prone mice, which facilitates us to understand the suppressive function of PD-1-PD-L1 axis in the pathogenesis and progress of the lupus nephritis, and to explore a possible effective therapeutic strategy to SLE.

scholarly journals Elevated Expression Levels of Inhibitory Receptor Programmed Death 1 on Simian Immunodeficiency Virus-Specific CD8 T Cells during Chronic Infection but Not after Vaccination

2007 ◽  
Vol 81 (11) ◽  
pp. 5819-5828 ◽  
Author(s):  
Vijayakumar Velu ◽  
Sunil Kannanganat ◽  
Chris Ibegbu ◽  
Lakshmi Chennareddi ◽  
Francois Villinger ◽  
...  
Keyword(s):  
T Cells ◽  
Simian Immunodeficiency Virus ◽  
Cd8 T Cells ◽  
Inhibitory Receptor ◽  
Programmed Death ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Programmed Death 1

ABSTRACT Here, we study the temporal expression of the inhibitory receptor programmed death 1 (PD-1) on simian immunodeficiency virus (SIV) Gag-specific T cells following pathogenic SIV infection or following vaccination with a DNA/modified vaccinia virus Ankara (DNA/MVA) vaccine and simian/human immunodeficiency virus (SHIV) challenge in macaques. Following infection, the majority (>95%) of Gag-specific CD8 T cells expressed PD-1, and the level of PD-1 expression per cell increased over time. The level of PD-1 expression in lymph nodes and rectal mucosal tissue, the major sites of virus replication, was higher compared to blood. In vitro blockade of PD-1 resulted in enhanced proliferation of SIV-specific CD8 as well as CD4 T cells. In contrast, following vaccination, the majority of peak effector Gag-specific CD8 T cells expressed low levels of PD-1, and these levels decreased further as the cells differentiated into memory cells. In addition, following SHIV challenge of these vaccinated macaques, the level of PD-1 expression on Gag-specific CD8 T cells correlated positively with plasma viremia. These results demonstrate that SIV-specific CD8 T cells express PD-1 after exposure to antigen but downregulate expression under conditions of antigen clearance and enhance expression under conditions of antigen persistence. They also demonstrate that the level of PD-1 expression per cell rather than the presence or absence of expression plays an important role in regulating CD8 T-cell dysfunction in pathogenic SIV infection. In addition, they demonstrate that similar to HIV infection, the PD-1:PD-1 ligand inhibitory pathway is operational in pathogenic SIV infection, and the macaque/SIV model would be ideal to test the safety and therapeutic benefit of blocking this pathway in vivo.

NFATc3 regulates the transcription of genes involved in T-cell activation and angiogenesis

Blood ◽  
2011 ◽  
Vol 118 (3) ◽  
pp. 795-803 ◽  
Author(s):  
Katia Urso ◽  
Arantzazu Alfranca ◽  
Sara Martínez-Martínez ◽  
Amelia Escolano ◽  
Inmaculada Ortega ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Target Genes ◽  
Gene Knockout ◽  
Activated T Cells ◽  
Knock Down ◽  
And Function

Abstract The nuclear factor of activated T cells (NFAT) family of transcription factors plays important roles in many biologic processes, including the development and function of the immune and vascular systems. Cells usually express more than one NFAT member, raising the question of whether NFATs play overlapping roles or if each member has selective functions. Using mRNA knock-down, we show that NFATc3 is specifically required for IL2 and cyclooxygenase-2 (COX2) gene expression in transformed and primary T cells and for T-cell proliferation. We also show that NFATc3 regulates COX2 in endothelial cells, where it is required for COX2, dependent migration and angiogenesis in vivo. These results indicate that individual NFAT members mediate specific functions through the differential regulation of the transcription of target genes. These effects, observed on short-term suppression by mRNA knock-down, are likely to have been masked by compensatory effects in gene-knockout studies.

scholarly journals Programmed death 1 is highly expressed on CD8+CD57+T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein-Barr virus

Immunology ◽  
2017 ◽  
Vol 152 (4) ◽  
pp. 660-676 ◽  
Author(s):  
Maria T. Cencioni ◽  
Roberta Magliozzi ◽  
Richard Nicholas ◽  
Rehiana Ali ◽  
Omar Malik ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Cytotoxic Response ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Epstein Barr
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