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 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 Immune checkpoint dysfunction in large and medium vessel vasculitis

2017 ◽  
Vol 312 (5) ◽  
pp. H1052-H1059 ◽  
Author(s):  
Ryu Watanabe ◽  
Hui Zhang ◽  
Gerald Berry ◽  
Jörg J. Goronzy ◽  
Cornelia M. Weyand
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Intimal Hyperplasia ◽  
Cd4 T Cells ◽  
Vessel Wall ◽  
Checkpoint Inhibitors ◽  
Cell Death Protein

Giant cell arteritis (GCA) is a granulomatous vasculitis of the aorta and its medium-sized branch vessels. CD4 T cells, macrophages, and dendritic cells (DCs) build granulomatous infiltrates that injure the vessel wall and elicit a maladaptive response to injury. Pathological consequences include fragmentation of elastic membranes, destruction of the medial layer, microvascular neoangiogenesis, massive outgrowth of myofibroblasts, and lumen-occlusive intimal hyperplasia. Antigens have been suspected to drive the local activation of vasculitogenic CD4 T cells, but recent data have suggested a more generalized defect in the threshold setting of such T cells, rendering them hyperreactive. Under physiological conditions, immune checkpoints provide negative signals to curb T cell activation and prevent inflammation-associated tissue destruction. This protective mechanism is disrupted in GCA. Vessel wall DCs fail to express the immunoinhibitory ligand programmed cell death ligand-1, leaving lesional T cells unchecked. Consequently, programmed cell death protein-1-positive CD4 T cells can enter the immunoprivileged vessel wall, where they produce a broad spectrum of inflammatory cytokines (interferon-γ, IL-17, and IL-21) and have a direct role in driving intimal hyperplasia and intramural neoangiogenesis. The deficiency of the programmed cell death protein-1 immune checkpoint in GCA, promoting unopposed T cell immunity, contrasts with checkpoint hyperactivity in cancer patients in whom excessive programmed cell death ligand-1 expression paralyzes the function of antitumor T cells. Excessive checkpoint activity is the principle underlying cancer-immune evasion and is therapeutically targeted by immunotherapy with checkpoint inhibitors. Such checkpoint inhibitors, which unleash anticancer T cells and induce immune-related toxicity, may lead to drug-induced vasculitis.

scholarly journals Skeletal muscle antagonizes antiviral CD8+ T cell exhaustion

2020 ◽  
Vol 6 (24) ◽  
pp. eaba3458 ◽  
Author(s):  
Jingxia Wu ◽  
Nina Weisshaar ◽  
Agnes Hotz-Wagenblatt ◽  
Alaa Madi ◽  
Sicong Ma ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
T Cells ◽  
T Cell ◽  
Muscle Mass ◽  
Lymphoid Tissues ◽  
Proliferative Potential ◽  
T Cell Exhaustion ◽  
Chronic Infections ◽  
Cell Exhaustion ◽  
Body Weight Reduction

CD8+ T cells become functionally impaired or “exhausted” in chronic infections, accompanied by unwanted body weight reduction and muscle mass loss. Whether muscle regulates T cell exhaustion remains incompletely understood. We report that mouse skeletal muscle increased interleukin (IL)–15 production during LCMV clone 13 chronic infection. Muscle-specific ablation of Il15 enhanced the CD8+ T cell exhaustion phenotype. Muscle-derived IL-15 was required to maintain a population of CD8+CD103+ muscle-infiltrating lymphocytes (MILs). MILs resided in a less inflamed microenvironment, expressed more T cell factor 1 (Tcf1), and had higher proliferative potential than splenic T cells. MILs differentiated into functional effector T cells after reentering lymphoid tissues. Increasing muscle mass via muscle-specific inhibition of TGFβ signaling enhanced IL-15 production and antiviral CD8+ T cell responses. We conclude that skeletal muscle antagonizes T cell exhaustion by protecting T cell proliferative potential from inflammation and replenishing the effector T cell progeny pool in lymphoid organs.

scholarly journals Beyond T Cells: Understanding the Role of PD-1/PD-L1 in Tumor-Associated Macrophages

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Di Lu ◽  
Zhen Ni ◽  
Xiguang Liu ◽  
Siyang Feng ◽  
Xiaoying Dong ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Cell Activation ◽  
Suppressive Effect ◽  
And Function ◽  
Cell Death Protein

Programmed cell death protein 1 (PD-1) and its ligand PD-L1 have attracted wide attention from researchers in the field of immunotherapy. PD-1/PD-L1 have been shown to exist in many types of cells in addition to T lymphocytes, and studies have accordingly extended from their suppressive effect on T cell activation and function to examining their role in other cells. In this review, we summarize recent research on PD-1/PD-L1 in macrophages, with the aim of furthering our understanding of PD-1/PD-L1 and their detailed roles in macrophages. This information may provide additional insights for researchers, enrich the basic theory of anti-PD-1/PD-L1 immunotherapy, and thus ultimately benefit more patients.

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 Tim-3 adaptor protein Bat3 is a molecular checkpoint of T cell terminal differentiation and exhaustion

2021 ◽  
Vol 7 (18) ◽  
pp. eabd2710
Author(s):  
Chen Zhu ◽  
Karen O. Dixon ◽  
Kathleen Newcomer ◽  
Guangxiang Gu ◽  
Sheng Xiao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adaptor Protein ◽  
Transcriptional Analysis ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Dysfunction ◽  
Autoreactive T Cell ◽  
Autoimmune Conditions ◽  
T Cell Dysfunction

T cell exhaustion has been associated with poor prognosis in persistent viral infection and cancer. Conversely, in the context of autoimmunity, T cell exhaustion has been favorably correlated with long-term clinical outcome. Understanding the development of exhaustion in autoimmune settings may provide underlying principles that can be exploited to quell autoreactive T cells. Here, we demonstrate that the adaptor molecule Bat3 acts as a molecular checkpoint of T cell exhaustion, with deficiency of Bat3 promoting a profound exhaustion phenotype, suppressing autoreactive T cell–mediated neuroinflammation. Mechanistically, Bat3 acts as a critical mTORC2 inhibitor to suppress Akt function. As a result, Bat3 deficiency leads to increased Akt activity and FoxO1 phosphorylation, indirectly promoting Prdm1 expression. Transcriptional analysis of Bat3−/− T cells revealed up-regulation of dysfunction-associated genes, concomitant with down-regulation of genes associated with T cell effector function, suggesting that absence of Bat3 can trigger T cell dysfunction even under highly proinflammatory autoimmune conditions.

Combination cancer immunotherapy targeting PD-1 and GITR can rescue CD8+T cell dysfunction and maintain memory phenotype

2018 ◽  
Vol 3 (29) ◽  
pp. eaat7061 ◽  
Author(s):  
Bei Wang ◽  
Wen Zhang ◽  
Vladimir Jankovic ◽  
Jacquelynn Golubov ◽  
Patrick Poon ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
Cancer Immunotherapy ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Checkpoint Inhibition ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Most patients with cancer do not develop durable antitumor responses after programmed cell death protein 1 (PD-1) or programmed cell death ligand 1(PD-L1) checkpoint inhibition monotherapy because of an ephemeral reversal of T cell dysfunction and failure to promote long-lasting immunological T cell memory. Activating costimulatory pathways to induce stronger T cell activation may improve the efficacy of checkpoint inhibition and lead to durable antitumor responses. We performed single-cell RNA sequencing of more than 2000 tumor-infiltrating CD8+T cells in mice receiving both PD-1 and GITR (glucocorticoid-induced tumor necrosis factor receptor–related protein) antibodies and found that this combination synergistically enhanced the effector function of expanded CD8+T cells by restoring the balance of key homeostatic regulators CD226 and T cell immunoreceptor with Ig and ITIM domains (TIGIT), leading to a robust survival benefit. Combination therapy decreased CD8+T cell dysfunction and induced a highly proliferative precursor effector memory T cell phenotype in a CD226-dependent manner. PD-1 inhibition rescued CD226 activity by preventing PD-1–Src homology region 2 (SHP2) dephosphophorylation of the CD226 intracellular domain, whereas GITR agonism decreased TIGIT expression. Unmasking the molecular pathways driving durable antitumor responses will be essential to the development of rational approaches to optimizing cancer immunotherapy.

scholarly journals Partial restoration of immune response in Hepatitis C patients after viral clearance by direct-acting antiviral therapy

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0254243
Author(s):  
Meritxell Llorens-Revull ◽  
Maria Isabel Costafreda ◽  
Angie Rico ◽  
Mercedes Guerrero-Murillo ◽  
Maria Eugenia Soria ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Hepatitis C ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Clearance ◽  
Cd4 T Cell ◽  
Care Hospital ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

Background & aims HCV CD4+ and CD8+ specific T cells responses are functionally impaired during chronic hepatitis C infection. DAAs therapies eradicate HCV infection in more than 95% of treated patients. However, the impact of HCV elimination on immune responses remain controversial. Here, we aimed to investigate whether HCV cure by DAAs could reverse the impaired immune response to HCV. Methods We analyzed 27 chronic HCV infected patients undergoing DAA treatment in tertiary care hospital, and we determined the phenotypical and functional changes in both HCV CD8+ and CD4+ specific T-cells before and after viral clearance. PD-1, TIM-3 and LAG-3 cell-surface expression was assessed by flow cytometry to determine CD4+ T cell exhaustion. Functional responses to HCV were analyzed by IFN-Ɣ ELISPOT, intracellular cytokine staining (IL-2 and IFN-Ɣ) and CFSE-based proliferation assays. Results We observed a significant decrease in the expression of PD-1 in CD4+ T-cells after 12 weeks of viral clearance in non-cirrhotic patients (p = 0.033) and in treatment-naive patients (p = 0.010), indicating a partial CD4 phenotype restoration. IFN-Ɣ and IL-2 cytokines production by HCV-specific CD4+ and CD8+ T cells remained impaired upon HCV eradication. Finally, a significant increase of the proliferation capacity of both HCV CD4+ and CD8+ specific T-cells was observed after HCV elimination by DAAs therapies. Conclusions Our results show that in chronically infected patients HCV elimination by DAA treatment lead to partial reversion of CD4+ T cell exhaustion. Moreover, proliferative capacity of HCV-specific CD4+ and CD8+ T cells is recovered after DAA’s therapies.

scholarly journals Exhausted CD8+T Cells in the Tumor Immune Microenvironment: New Pathways to Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Weiqin Jiang ◽  
Yinjun He ◽  
Wenguang He ◽  
Guosheng Wu ◽  
Xile Zhou ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Burden ◽  
Effector Function ◽  
T Cell Exhaustion ◽  
Immune Microenvironment ◽  
Cell Exhaustion ◽  
Combination Strategies ◽  
Cell Pool ◽  
Tumor Immune Microenvironment

Tumor-specific CD8+T cells are exposed to persistent antigenic stimulation which induces a dysfunctional state called “exhaustion.” Though functioning to limit damage caused by immune response, T cell exhaustion leads to attenuated effector function whereby cytotoxic CD8+T cells fail to control tumor progression in the late stage. This pathway is a dynamic process from activation to “progenitor exhaustion” through to “terminally exhaustion” with distinct properties. With the rapid development of immunotherapy via enhancing T cell function, new studies are dissecting the mechanisms and identifying specific biomarkers of dynamic differentiation during the process of exhaustion. Further, although immune checkpoint inhibitors (ICIs) have achieved great success in clinical practice, most patients still show limited efficacy to ICIs. The expansion and differentiation of progenitor exhausted T cells explained the success of ICIs while the depletion of the progenitor T cell pool and the transient effector function of terminally exhausted T cells accounted for the failure of immune monotherapy in the context of exorbitant tumor burden. Thus, combination strategies are urgent to be utilized based on the reduction of tumor burden or the expansion of the progenitor T cell pool. In this review, we aim to introduce the concept of homeostasis of the activated and exhausted status of CD8+T cells in the tumor immune microenvironment, and present recent findings on dynamic differentiation process during T cell exhaustion and the implications for combination strategies in immune therapy.

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