scholarly journals Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis

Critical Care ◽  
2014 ◽  
Vol 18 (1) ◽  
pp. R3 ◽  
Author(s):  
Katherine Chang ◽  
Catherine Svabek ◽  
Cristina Vazquez-Guillamet ◽  
Bryan Sato ◽  
David Rasche ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Programmed Cell Death 1

scholarly journals Parasite-Derived Arginase Influences Secondary Anti-LeishmaniaImmunity by Regulating Programmed Cell Death-1–Mediated CD4+T Cell Exhaustion

2013 ◽  
Vol 190 (7) ◽  
pp. 3380-3389 ◽  
Author(s):  
Zhirong Mou ◽  
Helen M. Muleme ◽  
Dong Liu ◽  
Ping Jia ◽  
Ifeoma B. Okwor ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
Cd4 T Cell ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Programmed Cell Death 1

scholarly journals PD1 pathway in immune-mediated myopathies

2019 ◽  
Vol 6 (3) ◽  
pp. e558 ◽  
Author(s):  
Samuel Knauss ◽  
Corinna Preusse ◽  
Yves Allenbach ◽  
Sarah Leonard-Louis ◽  
Mehdi Touat ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Immune Mediated ◽  
Muscle Biopsies ◽  
Cell Death Protein

ObjectiveTo investigate the relevance of dysfunctional T cells in immune-mediated myopathies. We analyzed T-cell exhaustion and senescence, in the context of programmed cell death protein 1 (PD1)-related immunity in skeletal muscle biopsies from patients with immune-mediated necrotizing myopathy (IMNM), sporadic inclusion body myositis (sIBM), and myositis induced by immune checkpoint inhibitors (irMyositis).MethodsSkeletal muscle biopsies from 12 patients with IMNM, 7 patients with sIBM, and 8 patients with irMyositis were analyzed by immunostaining and immunofluorescence as well as by quantitative PCR. Eight biopsies from nondisease participants served as controls.ResultsCD3+CD8+ T cells in biopsies from IMNM, sIBM, and irMyositis were largely PD1-positive, while CD68+ macrophages were sparsely positive to the ligand of programmed cell death protein 1 (PD-L1). The sarcolemma of myofibers was PD-L2+ and was colocalized with major histocompatibility complex (MHC) class I. CD68+ macrophages were colocalized with PD-L2. Senescent T cells were strongly enriched in skeletal muscle of sIBM, revealing a distinct immunologic signature. Biopsies from patients with irMyositis showed mild signs of senescence and exhaustion.ConclusionPersistent exposure to antigens in IMNMs and sIBM may lead to T-cell exhaustion, a process controlled by the PD1 receptor and its cognate ligands PD-L1/PD-L2. To our knowledge, these data are the first evidence of presence of dysfunctional T cells and relevance of the PD1 pathway in IMNM, sIBM, and irMyositis. These findings may guide the way to a novel understanding of the immune pathogenesis of immune-mediated myopathies.

scholarly journals Expression of Programmed Cell Death 1 (PD-1) As a Marker of T- Cell Exhaustion and Its Correlation with Interleukin -10 Serum Level in Patients with COVID-19

2021 ◽  
Author(s):  
Dalia M. Ibrahim ◽  
Fatma M. Mahmoud ◽  
Wafaa K. Zaki ◽  
Amr H. Hamza ◽  
Nadia M. ElSheshtawy
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Lymphocytes ◽  
Programmed Cell Death ◽  
Serum Levels ◽  
Interleukin 10 ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Patient Groups

Coronavirus disease 2019 (COVID-19), which is a major global concern, is characterized by a progressive disease pattern involving diverse host immune responses. Programmed cell death marker-1(PD-1) expression, a critical checkpoint for T cell exhaustion, can be modulated by interleukin-10, which also mediates apoptotic T cell cytopenia. We aimed to measure the level of PD-1 expression and to investigate its correlation with IL-10 serum levels in modulating T cell effector function, correlating the results with the level of severity of the disease. This study involved 40 patients with COVID-19 and 20 healthy controls. Using flow cytometry, the expression of PD-1 was determined on CD8+ T lymphocytes and CD4+ T lymphocytes. ELISA was used to determine the levels of IL-10 in the serum. We found a remarkable decrease in T cell counts with functionally exhausted surviving T cells in the patient groups, especially in patients with severe disease. PD-1 expression increased significantly in CD4+, CD8+, and total T cells, showing a higher expression in CD8+ T cells. The patient groups had significantly higher serum IL-10 levels than the control group. The ROC analysis demonstrated the predictive role of IL-10 levels in disease severity (65% sensitivity, 80% specificity, and AUC = 0.806). IL-10 serum levels and PD-1 expression in total T cells were positively correlated, suggesting that IL-10 participates in T cell exhaustion.

scholarly journals Co-delivery of IOX1 and doxorubicin for antibody-independent cancer chemo-immunotherapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Liu ◽  
Zhihao Zhao ◽  
Nasha Qiu ◽  
Quan Zhou ◽  
Guowei Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
Memory Function ◽  
Histone Demethylase ◽  
Cell Dysfunction ◽  
T Cell Infiltration ◽  
Programmed Cell Death 1 ◽  
T Cell Dysfunction

AbstractAnti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibodies are currently used in the clinic to interupt the PD-1/PD-L1 immune checkpoint, which reverses T cell dysfunction/exhaustion and shows success in treating cancer. Here, we report a histone demethylase inhibitor, 5-carboxy-8-hydroxyquinoline (IOX1), which inhibits tumour histone demethylase Jumonji domain-containing 1A (JMJD1A) and thus downregulates its downstream β-catenin and subsequent PD-L1, providing an antibody-independent paradigm interrupting the PD-1/PD-L1 checkpoint. Synergistically, IOX1 inhibits cancer cells’ P-glycoproteins (P-gp) through the JMJD1A/β-catenin/P-gp pathway and greatly enhances doxorubicin (DOX)-induced immune-stimulatory immunogenic cell death. As a result, the IOX1 and DOX combination greatly promotes T cell infiltration and activity and significantly reduces tumour immunosuppressive factors. Their liposomal combination reduces the growth of various murine tumours, including subcutaneous, orthotopic, and lung metastasis tumours, and offers a long-term immunological memory function against tumour rechallenging. This work provides a small molecule-based potent cancer chemo-immunotherapy.

scholarly journals Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

2012 ◽  
Vol 209 (6) ◽  
pp. 1201-1217 ◽  
Author(s):  
Tadashi Yokosuka ◽  
Masako Takamatsu ◽  
Wakana Kobayashi-Imanishi ◽  
Akiko Hashimoto-Tane ◽  
Miyuki Azuma ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tyrosine Phosphatase ◽  
Cell Receptor ◽  
Programmed Cell Death 1

Programmed cell death 1 (PD-1) is a negative costimulatory receptor critical for the suppression of T cell activation in vitro and in vivo. Single cell imaging elucidated a molecular mechanism of PD-1–mediated suppression. PD-1 becomes clustered with T cell receptors (TCRs) upon binding to its ligand PD-L1 and is transiently associated with the phosphatase SHP2 (Src homology 2 domain–containing tyrosine phosphatase 2). These negative costimulatory microclusters induce the dephosphorylation of the proximal TCR signaling molecules. This results in the suppression of T cell activation and blockade of the TCR-induced stop signal. In addition to PD-1 clustering, PD-1–TCR colocalization within microclusters is required for efficient PD-1–mediated suppression. This inhibitory mechanism also functions in PD-1hi T cells generated in vivo and can be overridden by a neutralizing anti–PD-L1 antibody. Therefore, PD-1 microcluster formation is important for regulation of T cell activation.

scholarly journals Programmed Cell Death-1: Programmed Cell Death-Ligand 1 Interaction Protects Human Cardiomyocytes Against T-Cell Mediated Inflammation and Apoptosis Response In Vitro

2020 ◽  
Vol 21 (7) ◽  
pp. 2399
Author(s):  
Woan Ting Tay ◽  
Yi-Hsien Fang ◽  
Suet Theng Beh ◽  
Yen-Wen Liu ◽  
Ling-Wei Hsu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
T Cell ◽  
T Lymphocytes ◽  
Programmed Cell Death ◽  
T Cell Response ◽  
Tumor Bearing ◽  
Cd8 T Lymphocytes ◽  
Programmed Cell Death 1

Aim: Immunological checkpoint therapy is considered a powerful method for cancer therapy and acts by re-activating autologous T cells to kill the cancer cell. Myocarditis cases have been reported in cancer patients after immunological therapy; for example, nivolumab treatment is a monoclonal antibody that blocks programmed cell death-1/programmed cell death ligand-1 ligand interaction. This project provided insight into the inflammatory response as a benchmark to investigate the potential cardiotoxic effect of T cell response to the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis in regulating cardiomyocyte injury in vitro. Methods and Results: We investigated cardiomyopathy resulted from the PD-1/PD-L1 axis blockade using the anti-PD-1 antibody in Rockefeller University embryonic stem cells-derived cardiomyocytes (RUES2-CMs) and a melanoma tumor-bearing murine model. We found that nivolumab alone did not induce inflammatory-related proteins, including PD-L1 expression, and did not induce apoptosis, which was contrary to doxorubicin, a cardiotoxic chemotherapy drug. However, nivolumab was able to exacerbate the immune response by increasing cytokine and inflammatory gene expression in RUES2-CMs when co-cultured with CD4+ T lymphocytes and induced apoptosis. This effect was not observed when RUES2-CMs were co-cultured with CD8+ T lymphocytes. The in vivo model showed that the heart function of tumor-bearing mice was decreased after treatment with anti-PD-1 antibody and demonstrated a dilated left ventricle histological examination. The dilated left ventricle was associated with an infiltration of CD4+ and CD8+ T lymphocytes into the myocardium. PD-L1 and inflammatory-associated gene expression were significantly increased in anti-PD-1-treated tumor-bearing mice. Cleaved caspase-3 and mouse plasma cardiac troponin I expressions were increased significantly. Conclusion: PD-L1 expression on cardiomyocytes suppressed T-cell function. Blockade of PD-1 by nivolumab enhanced cardiomyocyte inflammation and apoptosis through the enhancement of T-cell response towards cardiomyocytes.

Programmed Cell Death 1 and Programmed Cell Death Ligands in Extranodal Natural Killer/T Cell Lymphoma: Expression Pattern and Potential Prognostic Relevance

2019 ◽  
Vol 143 (1) ◽  
pp. 78-88 ◽  
Author(s):  
Hamidah Muhamad ◽  
Narittee Suksawai ◽  
Thamatorn Assanasen ◽  
Chantana Polprasert ◽  
Udomsak Bunworasate ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
Natural Killer ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Lymphoma Cells ◽  
Natural Killer T Cell ◽  
Programmed Cell Death 1 ◽  
Killer T Cell

The programmed cell death 1/programmed cell death ligands (PD-1/PD-Ls) axis is a potential immune escape mechanism of cancers. However, data on the PD-1/PD-Ls pathway in EBV-associated extranodal natural killer/T cell lymphoma (ENKTL) and its clinical implication are limited. Herein, we characterized PD-1/PD-L expression and its prognosis relevance in 49 ENKTL patients in Thailand. PD-L1 was expressed frequently on both lymphoma cells (61.2%) and stroma (77.5%), whereas PD-L2 expression was more common on lymphoma (63.2%) than stromal cells. PD-1 was positive in 20.5% of stroma, but undetectable on lymphoma cells. There was no association between baseline clinical characteristics and the expression PD-1/PD-Ls. The survival of patients with PD-Ls on tumor cells was poor. For PD-L1-positive versus negative cases, the 2-year event-free survival (EFS) was 42.2 versus 71.8% (p = 0.03) and 2-year overall survival (OS) was 45.4 versus 78.9% (p = 0.02), respectively. Comparing between patients with PD-L2-positive and PD-L2-negative lymphoma, the 2-year EFS was 37.1 versus 82.4% (p = 0.02) and 2-year OS was 45.2 versus 82.4% (p = 0.03), respectively. Neither PD-1 nor PD-Ls expression in the stroma predicted outcomes. In conclusion, PD-Ls were frequently expressed on ENKTL cells and associated with inferior outcomes. Therefore, PD-Ls are potential prognostic biomarkers and the roles of immune checkpoint blockade therapy in ENKTL deserve further investigation.

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