18
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Liver-Mediated Adaptive Immune Tolerance

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The liver is an immunologically tolerant organ that is uniquely equipped to limit hypersensitivity to food-derived antigens and bacterial products through the portal vein and can feasibly accept liver allografts. The adaptive immune response is a major branch of the immune system that induces organ/tissue-localized and systematic responses against pathogens and tumors while promoting self-tolerance. Persistent infection of the liver with a virus or other pathogen typically results in tolerance, which is a key feature of the liver. The liver's immunosuppressive microenvironment means that hepatic adaptive immune cells become readily tolerogenic, promoting the death of effector cells and the “education” of regulatory cells. The above mechanisms may result in the clonal deletion, exhaustion, or inhibition of peripheral T cells, which are key players in the adaptive immune response. These tolerance mechanisms are believed to be responsible for almost all liver diseases. However, optimal protective adaptive immune responses may be achieved through checkpoint immunotherapy and the modulation of hepatic innate immune cells in the host. In this review, we focus on the mechanisms involved in hepatic adaptive immune tolerance, the liver diseases caused thereby, and the therapeutic strategies needed to overcome this tolerance.

          Related collections

          Most cited references98

          • Record: found
          • Abstract: found
          • Article: found

          CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer

          Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, metabolic dysregulation, poor memory recall and homeostatic self-renewal, and distinct transcriptional and epigenetic programs. The ability to reinvigorate Tex cells through inhibitory receptor blockade, such as αPD-1, highlights the therapeutic potential of targeting this population. Emerging insights into the mechanisms of exhaustion are informing immunotherapies for cancer and chronic infections. However, like other immune cells, Tex cells are heterogeneous and include progenitor and terminal subsets with unique characteristics and responses to checkpoint blockade. Here, we review our current understanding of Tex cell biology, including the developmental paths, transcriptional and epigenetic features, and cell intrinsic and extrinsic factors contributing to exhaustion and how this knowledge may inform therapeutic targeting of Tex cells in chronic infections, autoimmunity, and cancer.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells

            Summary Checkpoint inhibitors have revolutionized cancer treatment. However, only a minority of patients respond to these immunotherapies. Here, we report that blocking the inhibitory NKG2A receptor enhances tumor immunity by promoting both natural killer (NK) and CD8+ T cell effector functions in mice and humans. Monalizumab, a humanized anti-NKG2A antibody, enhanced NK cell activity against various tumor cells and rescued CD8+ T cell function in combination with PD-x axis blockade. Monalizumab also stimulated NK cell activity against antibody-coated target cells. Interim results of a phase II trial of monalizumab plus cetuximab in previously treated squamous cell carcinoma of the head and neck showed a 31% objective response rate. Most common adverse events were fatigue (17%), pyrexia (13%), and headache (10%). NKG2A targeting with monalizumab is thus a novel checkpoint inhibitory mechanism promoting anti-tumor immunity by enhancing the activity of both T and NK cells, which may complement first-generation immunotherapies against cancer.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection.

              Dysfunctional CD8+ T cells present in chronic virus infections can express programmed death 1 (PD-1) molecules, and the inhibition of the engagement of PD-1 with its ligand (PD-L1) has been reported to enhance the antiviral function of these T cells. We took advantage of the wide fluctuations in levels of viremia which are typical of chronic hepatitis B virus (HBV) infection to comprehensively analyze the impact of prolonged exposure to different virus quantities on virus-specific T-cell dysfunction and on its reversibility through the blocking of the PD-1/PD-L1 pathway. We confirm that chronic HBV infection has a profound effect on the HBV-specific T-cell repertoire. Despite the use of a comprehensive panel of peptides covering all HBV proteins, HBV-specific T cells were rarely observed directly ex vivo in samples from patients with chronic infection, in contrast to those from patients with acute HBV infection. In chronic HBV infection, virus-specific T cells were detected mainly in patients with lower levels of viremia. These HBV-specific CD8+ T cells expressed PD-1, and their function was improved by the blocking of PD-1/PD-L1 engagement. Thus, a broad spectrum of anti-HBV immunity is expressed by patients with chronic HBV infection and this spectrum is proportional to HBV replication levels and can be improved by blocking the PD-1/PD-L1 pathway. This information may be useful for the design of immunotherapeutic strategies to complement and optimize available antiviral therapies.
                Bookmark

                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                05 November 2019
                2019
                : 10
                : 2525
                Affiliations
                [1] 1Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University , Hefei, China
                [2] 2Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Molecular Medicine, School of Life Sciences, University of Science and Technology of China , Hefei, China
                [3] 3Institute of Immunology, University of Science and Technology of China , Hefei, China
                Author notes

                Edited by: Yuan Quan, Xiamen University, China

                Reviewed by: Robert Thimme, University of Freiburg, Germany; Cai Zhang, Shandong University, China

                *Correspondence: Zhigang Tian tzg@ 123456ustc.edu.cn

                This article was submitted to Viral Immunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2019.02525
                6856635
                31787967
                aa04bc53-f4ba-4a57-882a-d986db32682e
                Copyright © 2019 Zheng and Tian.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 24 June 2019
                : 10 October 2019
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 149, Pages: 12, Words: 10695
                Funding
                Funded by: Ministry of Science and Technology of China
                Award ID: 2018YFA0507403
                Funded by: Chinese Academy of Sciences
                Award ID: XDB29030201
                Funded by: National Natural Science Foundation of China
                Award ID: 81788101
                Award ID: 81821001
                Award ID: 91542000
                Award ID: 81771685
                Categories
                Immunology
                Review

                Immunology
                liver tolerance,t cell dysfunction,innate cell dysfunction,immune regulation,liver-draining lymph node,liver diseases

                Comments

                Comment on this article