PD-1 Blockage Reverses Immune Dysfunction and Hepatitis B Viral Persistence in a Mouse Animal Model

Tzeng, Horng Tay; Tsai, Hwei-Fang; Liao, Hsiu Jung; Lin, Yi; Chen, Lieping; Chen, Pei‐Jer; Hsu, Ping–I

doi:10.1371/journal.pone.0039179

Cited by 125 publications

(95 citation statements)

References 26 publications

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“…The upregulation of PD-1 is a typical sign of T cell exhaustion. Previous studies indicated that elevated expression of PD-1 has a close relationship with immune defects in chronic viral infection, tumor, and aging [21-24], and blockade of PD-1 pathways was observed to restore the T cell functional defects in both chronic virus infection and tumor models [21, 22, 24-27]. In addition, T cell exhaustion appears to be correlated with a higher antigen load, persistent exposure to antigens, and decreased specific CD4 + T cells [28].…”

Section: Introductionmentioning

confidence: 99%

Acute Traumatic Brain Injury Induces CD4+ and CD8+ T Cell Functional Impairment by Upregulating the Expression of PD-1 via the Activated Sympathetic Nervous System

Yang

Chen

et al. 2019

Neuroimmunomodulation

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Objective: Traumatic brain injury (TBI) induces immunosuppression in the acute phase, and the activation of the sympathetic nervous system (SNS) might play a role in this process, but the mechanism involved is unknown. Herein, we explored the impact of acute (a)TBI on the peripheral immune system and its correlation with the SNS and the T cell exhaustion marker, PD-1 (programmed cell death-1). Methods: Flow cytometry (FCM) was performed to analyze the expression of T cell markers and intracellular cytokines, interferon-γ and tumor necrosis factor-α, and the T cell exhaustion marker, PD-1, in the peripheral blood mononuclear cells (PBMCs) of TBI rats. Enzyme-linked immunosorbent assay (ELISA) was performed to analyze the concentration of norepinephrine (NE) in the serum. Propranolol was administrated to block the SNS in vivo and NE stimulation was used to imitate the activation of the SNS in vitro. Results: We found that the concentration of NE was significantly elevated after TBI, and the dysfunction of CD4⁺ and CD8⁺ T cells was reversed by the SNS blocker propranolol in vivo and imitated by the SNS neurotransmitter NE in vitro. The expression of PD-1 on CD4⁺ and CD8⁺ T cells was upregulated after aTBI, which was reversed by propranolol administration in vivo and imitated by NE stimulation in vitro. Furthermore, the PD-1 blocker reversed the dysfunction of CD4⁺ and CD8⁺T cells in vitro. Conclusion: Our findings demonstrated that aTBI activated the SNS, and further upregulated the expression of PD-1 on CD4⁺ and CD8⁺ T cells, which, in turn, impaired their function and contributed to immunosuppression.

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Section: Introductionmentioning

confidence: 99%

Acute Traumatic Brain Injury Induces CD4+ and CD8+ T Cell Functional Impairment by Upregulating the Expression of PD-1 via the Activated Sympathetic Nervous System

Yang

Chen

et al. 2019

Neuroimmunomodulation

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“…Liver tolerance can be observed even during chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, which usually induces CTL dysfunction and impaired responses to vaccination, resulting in ∼350 million chronic HBV-carrier people worldwide; thus, it is a major global health problem (2). In HBV-carrier humans or mice, the number and function of HBV-specific CD8 + T cells are gradually reduced with impaired IFN-g and TNF-a production as well as upregulation of coinhibitory factors, such as PD-1; together, these changes are also characteristic of CD8 + T cell exhaustion (3)(4)(5). Previous studies showed that regulatory T cells (Tregs) might suppress the priming, activation, and proliferation of HBV-specific CD8 + T cells, and that Treg depletion restored T cell function and accelerated HBV clearance in patients and HBV-carrier mice (6).…”

mentioning

confidence: 99%

γδT Cells Drive Myeloid-Derived Suppressor Cell–Mediated CD8+ T Cell Exhaustion in Hepatitis B Virus–Induced Immunotolerance

Kong

Sun

Chen

et al. 2014

The Journal of Immunology

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The mechanisms of liver hepatitis B virus (HBV)–induced systemic immune tolerance are still elusive, and the role of γδT cells has not yet been described. We examined the function of γδT cells in HBV-carrier mice––immunocompetent mice with plasmid-mediated persistent HBV expression in the liver. In this study, we found that γδT cell deficiency led to a break in HBV-induced tolerance and subsequent recovery of hepatic HBV-specific CD8+ T cells. Of interest, IL-17−/− mice phenocopied TCRδ−/− mice in terms of losing HBV persistence, and adoptive transfer of γδT cells restored HBV-persistent expression in TCRδ−/− mice. We further observed that hepatic CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) play a major role in this mechanism, as they were significantly reduced in both HBV-carrier TCRδ−/− and IL-17−/− mice. MDSC numbers also recovered after adoptive transfer of γδT cells, particularly Vγ4+ T cells. Furthermore, anti-Gr1–mediated MDSC depletion in HBV-carrier mice accelerated HBV elimination from the host, whereas MDSCs transferred to γδT cell-deficient mice restored HBV-induced tolerance. Accordingly, inhibition of MDSCs by the arginase-1 inhibitor norNOHA enhanced the number of HBV-specific CD8+ T cells and promoted HBV clearance. We also observed enhanced CD8+ T cell number with a notable decline of MDSCs in TCRδ−/− mice compared with wild-type mice during the recombinant adeno-associated virus/HBV1.3 virus infection. Importantly, HBV-carrier TCRδ−/− mice not only exhibited increased anti-HBV CD8+ T cells but also markedly reduced MDSCs. Overall, the current study reveals that γδT cells play a previously unrecognized regulatory role in liver tolerance by mobilizing MDSC infiltration to the liver, leading to MDSC-mediated CD8+ T cell exhaustion.

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“…Zhang y colaboradores encontraron que en pacientes con VHB el 70% de los linfocitos T específicos para el virus eran positivos para PD-1 (54). Varios estudios han sido publicados al respecto, uno de ellos realizado en ratones con infección crónica por VHB demostró que los anticuerpos anti-PD-1 lograron revertir la disfunción inmune y ayudaron en cierta medida a depurar el virus (60% de negatividad para HBsAg en comparación con 20% en los controles) (55). Actualmente los anticuerpos anti PD-1 se utilizan para el cáncer y se encuentran en ensayos clínicos para la hepatitis crónica por VHC (56).…”

Section: Bloqueo De Señales Inmunoinhibidoras (Pd-1)unclassified

Tratamiento actual y nuevas terapias contra la infección crónica por el virus de la Hepatitis B

Echeverri

Caraballo

Marín

et al. 2017

Rev. Colomb. Gastroenterol.

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La infección crónica por el virus de la hepatitis B es un grave problema de salud pública a nivel mundial. Sus consecuencias llegan a ser mortales y el tratamiento actual no ofrece curación sino control de la enfermedad. Las principales limitantes para una cura son la dificultad para destruir el ADNccc del virus en el núcleo celular y la presencia de material genético viral integrado en el ADN de la célula hospedera. No obstante, hay múltiples frentes de investigación enfocados en encontrar una cura definitiva al potenciar la respuesta inmune del hospedero o al actuar directamente contra el virus y su ciclo de replicación. En este artículo se exponen los principales avances que se han realizado en este campo.

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PD-1 Blockage Reverses Immune Dysfunction and Hepatitis B Viral Persistence in a Mouse Animal Model

Cited by 125 publications

References 26 publications

Acute Traumatic Brain Injury Induces CD4<sup>+</sup> and CD8<sup>+</sup> T Cell Functional Impairment by Upregulating the Expression of PD-1 via the Activated Sympathetic Nervous System

Acute Traumatic Brain Injury Induces CD4<sup>+</sup> and CD8<sup>+</sup> T Cell Functional Impairment by Upregulating the Expression of PD-1 via the Activated Sympathetic Nervous System

γδT Cells Drive Myeloid-Derived Suppressor Cell–Mediated CD8+ T Cell Exhaustion in Hepatitis B Virus–Induced Immunotolerance

Tratamiento actual y nuevas terapias contra la infección crónica por el virus de la Hepatitis B

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