Upregulation of PD-1 on CD4+CD25+T cells is associated with immunosuppression in liver of mice infected with Echinococcus multilocularis

La, Xiaolin; Zhang, Fengbo; Li, Yanhua; Li, Jun; Guo, Yong; Zhao, Hui; Pang, Nannan; Ma, Xiumin; Wen, Hao; Fan, Haining; Ding, Jianbing

doi:10.1016/j.intimp.2015.04.013

Cited by 40 publications

(42 citation statements)

References 47 publications

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“…With regard to echinococcosis, significantly higher levels of sPD‐L1 in patients with cystic echinococcosis were observed compared with healthy controls, and elevated levels of Th2 cytokines in the sera of patients with CE . A recent study showed that upregulation of PD‐1 on CD4 + CD25 + T cells is associated with immunosuppression in liver of mice infected with E. multiloculari s . Echinococcus multilocularis proliferation and some malignant tumours are both sharing similar features such as local immune evasion, induction of tolerance and disruption of T cell signalling, and T cell exhaustion at late stage of infection .…”

Section: Introductionmentioning

confidence: 99%

Immunotherapy of alveolar echinococcosis via PD‐1/PD‐L1 immune checkpoint blockade in mice

Wang

Jebbawi

Bellanger

et al. 2018

Parasite Immunology

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Summary The growth potential of the tumour‐like Echinococcus multilocularis metacestode (causing alveolar echinococcosis, AE ) is directly dependent upon the nature/function of the periparasitic adaptive host immune‐mediated processes. PD ‐1/ PD ‐L1 pathway (programmed cell death 1), which inhibits lymphocytic proliferation in tumour development, is over‐expressed at the chronic stage of AE . We tested the impact of a PD ‐1/ PD ‐L1 pathway blockade on the outcome of both chronic AE (intraperitoneal metacestode inoculation, secondary AE and SAE ) and acute AE (peroral egg infection, primary AE and PAE ). To assess the parasite proliferation potential, we measured parasite mass weight for SAE and liver lesion number for PAE . In both models, the parasite load was significantly decreased in response to anti‐ PD ‐L1 antibody treatment. In SAE , anti‐ PDL 1 administration was associated with increased Th1 response parameters and decreased Treg responses, while in PAE anti‐ PDL 1 administration was associated with fewer lesions in the liver and decreased Treg/Th2 responses. Our findings highly suggested that a PD ‐1/ PD ‐L1 pathway blockade triggered the host immune responses in favour of an immune‐mediated control of E. multilocularis proliferation. Based on this, future studies that combine PD ‐1/ PD ‐L1 blockade with a parasitostatic albendazole medication may yield in a putatively curative therapeutic approach to control alveolar echinococcosis.

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Section: Introductionmentioning

confidence: 99%

Immunotherapy of alveolar echinococcosis via PD‐1/PD‐L1 immune checkpoint blockade in mice

Wang

Jebbawi

Bellanger

et al. 2018

Parasite Immunology

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“…Persistence of E. multilocularis is associated with a chronic granulomatous inflammation, leading to the disruption of the normal function of T cells, which is nowadays referred to as “functional exhaustion.” Recent reports have also shown that E. multilocularis infection is associated with the expression of “checkpoint” receptors that are known to limit the activity of parasite‐specific lymphocytes. We and others have shown that the receptors programmed cell‐death 1 (PDCD1), 2B4 (SLAMf4, CD244), and lymphocyte‐activation gene 3 (LAG3) are aberrantly expressed during chronic infection, and that they contribute to “exhausted” parasite‐induced T‐cell response and lead to the maintenance of E. multilocularis survival . Observations in humans and experimental studies in animals suggest that, in the absence of fully effective antiparasitic chemotherapy for AE, modulation of the host immune response, specifically, blocking the coinhibitory receptors (e.g., PDCD1), could be envisaged to fight against the parasite and to prevent the disease and/or its complications.…”

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confidence: 99%

“…Blockade of the PDCD1–programmed death ligand 1 (PD‐L1) pathway during Leishmania donovani rescued L. donovani –specific CD8 + T cells from exhaustion with increased interferon (IFN)‐γ production and reduced splenic parasite burden . With regard to echinococcosis, up‐regulation of PDCD1 is associated with immunosuppression in the livers of mice, and PDCD1 blockade triggers the host immune responses to control E. multilocularis growth . Although anti‐CTLA4 and anti‐PDCD1/PD‐L1 blockades have already been proven successful in oncology and in preclinical studies in parasite infections, their benefit is limited to susceptible tumors or parasites and does not cover all situations .…”

mentioning

confidence: 99%

Immune Exhaustion of T Cells in Alveolar Echinococcosis Patients and Its Reversal by Blocking Checkpoint Receptor TIGIT in a Murine Model

Zhang

Lin

et al. 2020

Hepatology

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Background and Aims The cestode Echinococcus multilocularis infection, a serious health problem worldwide, causes alveolar echinococcosis (AE), a tumor‐like disease predominantly located in the liver and able to spread to any organs. Until now, there have been few studies that explore how T‐cell exhaustion contributes to the parasite’s escape from immune attack and how it might be reversed. Approach and Results In this study, we found that liver T‐cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine‐based inhibitory motif domain (TIGIT) expression was significantly enhanced and positively correlated with lesion activity in AE patients. High TIGIT expression in both liver‐infiltrating and blood T cells was associated with their functional exhaustion, and its ligand CD155 was highly expressed by hepatocytes surrounding the infiltrating lymphocytes. In co‐culture experiments using human blood T cells and hepatic cell line HL‐7702, CD155 induced functional impairment of TIGIT+ T cells, and in vitro blockade with TIGIT antibody restored the function of AE patients’ T cells. Similar TIGIT‐related functional exhaustion of hepatic T cells and an abundant CD155 expression on hepatocytes were observed in E. multilocularis–infected mice. Importantly, in vivo blocking TIGIT prevented T‐cell exhaustion and inhibited disease progression in E. multilocularis–infected mice. Mechanistically, CD4+ T cells were totally and CD8+ T cells partially required for anti‐TIGIT–induced regression of parasite growth in mice. Conclusions This study demonstrates that E. multilocularis can induce T‐cell exhaustion through inhibitory receptor TIGIT, and that blocking this checkpoint may reverse the functional impairment of T cells and represent a possible approach to immunotherapy against AE.

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“…The development of regulatory responses includes the negative signalling between antigen‐presenting cells and T cells, in particular, through the PD‐1 pathway. One of the works above shows exacerbated expression of PD‐1 CD4 + T cells and its ligand PD‐L1 in dendritic cells in liver during chronic E. multilocularis infection; in addition, it mechanistically connects PD‐L1/PD‐1 with high TGF‐β, and also IL‐10, expression. Interestingly, CD28, the main receptor relaying activating signals from antigen‐presenting cells to T cells, is very strongly downregulated in the periphery of E. granulosus hydatids in human liver, in comparison with other liver pathologies …”

Section: How Do Larval Taeniids Evade Granulomatous Responses?mentioning

confidence: 96%

“…With respect to mechanisms that operate on the overall control of immunity, much recent information in Echinococcus infections points to a strong participation of Foxp3 + regulatory T cells and the regulatory and profibrotic cytokine TGF‐β . Two studies in mice show massive increase in local expression of TGF‐β pathway proteins in E. multilocularis ‐infected livers during the course of chronic infection, relating it to the fibrosis process.…”

Section: How Do Larval Taeniids Evade Granulomatous Responses?mentioning

confidence: 99%

Granulomatous responses in larval taeniid infections

Díaz

Sagasti

Casaravilla

2018

Parasite Immunology

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Granulomas are responses to persistent nonliving bodies or pathogens, centrally featuring specialized macrophage forms called epithelioid and multinucleated giant cells. The larval stages of the cestode parasites of the Taeniidae family (Taenia, Echinococcus) develop for years in fixed tissue sites in mammals. In consequence, they are targets of granulomatous responses. The information on tissue responses to larval taeniids is fragmented among host and parasite species and scattered over many decades. We attempt to draw an integrated picture of these responses in solid tissues. The intensity of inflammation around live parasites spans a spectrum from minimal to high, parasite vitality correlating with low inflammation. The low end of the inflammatory spectrum features collagen capsules proximal to the parasites and moderate distal infiltration. The middle of the spectrum is dominated by classical granulomatous responses, whereas the high end features massive eosinophil invasions. Across the range of parasite species, much observational evidence suggests that eosinophils are highly effective at killing larval taeniids in solid tissues, before and during chronic granulomatous responses. The evidence available also suggests that these parasites are adapted to inhibit host granulomatous responses, in part through the exacerbation of host regulatory mechanisms including regulatory T cells and TGF-β.

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Upregulation of PD-1 on CD4+CD25+T cells is associated with immunosuppression in liver of mice infected with Echinococcus multilocularis

Cited by 40 publications

References 47 publications

Immunotherapy of alveolar echinococcosis via PD‐1/PD‐L1 immune checkpoint blockade in mice

Immunotherapy of alveolar echinococcosis via PD‐1/PD‐L1 immune checkpoint blockade in mice

Immune Exhaustion of T Cells in Alveolar Echinococcosis Patients and Its Reversal by Blocking Checkpoint Receptor TIGIT in a Murine Model

Granulomatous responses in larval taeniid infections

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