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1
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Guo P, Zhong L, Wang T, Luo W, Zhou A, Cao D. NK cell-based immunotherapy for hepatocellular carcinoma: Challenges and opportunities. Scand J Immunol 2025; 101:e13433. [PMID: 39934640 DOI: 10.1111/sji.13433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 12/22/2024] [Accepted: 01/01/2025] [Indexed: 02/13/2025]
Abstract
Hepatocellular carcinoma (HCC) remains one of the most challenging malignancies globally, characterized by significant heterogeneity, late-stage diagnosis, and resistance to treatment. In recent years, the advent of immune-checkpoint blockades (ICBs) and targeted immune cell therapies has marked a substantial advancement in HCC treatment. However, the clinical efficacy of these existing therapies is still limited, highlighting the urgent need for new breakthroughs. Natural killer (NK) cells, a subset of the innate lymphoid cell family, have shown unique advantages in the anti-tumour response. With increasing evidence suggesting the crucial role of dysfunctional NK cells in the pathogenesis and progression of HCC, considerable efforts have been directed toward exploring NK cells as a potential therapeutic target for HCC. In this review, we will provide an overview of the role of NK cells in normal liver immunity and in HCC, followed by a detailed discussion of various NK cell-based immunotherapies and their potential applications in HCC treatment.
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Affiliation(s)
- Pei Guo
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Liyuan Zhong
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Tao Wang
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Weijia Luo
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Aiqiang Zhou
- Guangzhou Hospital of Integrated Chinese and Western Medicine, Guangzhou, Guangdong, P.R China
| | - Deliang Cao
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
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2
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Henriques-Pons A, Vacani-Martins N, dos Santos CDLP, Meuser-Batista M. The liver's dilemma: sensing real danger in a sea of PAMPs: the (arterial) sinusoidal segment theory. Front Immunol 2025; 15:1503063. [PMID: 39931578 PMCID: PMC11808282 DOI: 10.3389/fimmu.2024.1503063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 12/30/2024] [Indexed: 02/13/2025] Open
Abstract
The liver is susceptible to viruses and bacterial infections, tumors, and sterile tissue damage, but immunological danger recognition in the liver is highly unconventional. When analyzing innate and adaptive immunity in the organ, the valid concepts that guide danger recognition and immune response in the periphery should be put aside. In the liver, the vascular anatomy is a game changer, as about 80% of the blood that percolates the organ arrives from the hepatic portal vein, draining blood rich in molecules from the intestinal flora. This 24/7 exposure to high amounts of pathogen-associated molecular pattern (PAMPs) molecules results in hepatic immunological tolerance. In the liver, dendritic, Kupffer (KC), liver sinusoidal endothelial cells (LSECs), and even hepatocytes express PD-L1, a T lymphocyte downregulatory molecule. Most cells express Fas-L, IL-10, TGF-β, low levels of co-stimulatory molecules, lack of or have low levels of MHC-I and/or MHC-II expression. Moreover, other negative regulators such as CTLA-4, IDO-1, and prostaglandin E2 (PGE2) are regularly expressed. Then, how can real danger be discerned and recognized in this sea of PAMPs? This is an open question. Here, we hypothesize that conventional immunological danger recognition can occur in the liver but in specific and minor arterial sinusoidal segments,. Then, in the portal triad, where the hepatic artery ramificates into the stroma and carries arterial blood with no gut-derived PAMPs, there is no evolutive or environmental pressure for immunosuppressive pathways, and conventional immunological danger recognition could occur. Therefore, in arterial sinusoidal segments with no sea of PAMPs, the liver could recognize real danger and support innate and adaptive immunity.
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Affiliation(s)
- Andrea Henriques-Pons
- Laboratorio de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Natália Vacani-Martins
- Laboratorio de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | | | - Marcelo Meuser-Batista
- Laboratório de Educação Profissional em Técnicas Laboratoriais em Saúde, Escola Politecnica de Saúde Joaquim Venâncio, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
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3
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Zhang XC, Zhou YW, Wei GX, Luo YQ, Qiu M. Locoregional therapies combined with immune checkpoint inhibitors for liver metastases. Cancer Cell Int 2024; 24:302. [PMID: 39217341 PMCID: PMC11365172 DOI: 10.1186/s12935-024-03484-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) have achieved remarkable success in clinical research and practice. Notably, liver metastasis is not sensitive to ICIs. Liver locoregional therapies can cause irreversible damage to tumor cells and release tumor antigens, thereby providing a rationale for immunotherapy treatments in liver metastasis. The combination therapy of ICIs with locoregional therapies is a promising option for patients with liver metastasis. Preclinical studies have demonstrated that combining ICIs with locoregional therapies produces a significantly synergistic anti-tumor effect. However, the current evidence for the efficacy of ICIs combined with locoregional therapies remains insufficient. Therefore, we review the literature on the mechanisms of locoregional therapies in treating liver metastasis and the clinical research progress of their combination with ICIs.
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Affiliation(s)
- Xing-Chen Zhang
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, 610041, Sichuan Province, China
| | - Yu-Wen Zhou
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, 610041, Sichuan Province, China
| | - Gui-Xia Wei
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yi-Qiao Luo
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Meng Qiu
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, 610041, Sichuan Province, China.
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4
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Conway JW, Braden J, Lo SN, Scolyer RA, Carlino MS, Menzies AM, Long GV, da Silva IP. VEGF Inhibitors Improve Survival Outcomes in Patients with Liver Metastases across Cancer Types-A Meta-Analysis. Cancers (Basel) 2023; 15:5012. [PMID: 37894379 PMCID: PMC10605052 DOI: 10.3390/cancers15205012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 09/26/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Liver metastases are associated with poor prognosis across cancers. Novel treatment strategies to treat patients with liver metastases are needed. This meta-analysis aimed to assess the efficacy of vascular endothelial growth factor inhibitors in patients with liver metastases across cancers. METHODS A systematic search of PubMed, Cochrane CENTRAL, and Embase was performed between January 2000 and April 2023. Randomized controlled trials of patients with liver metastases comparing standard of care (systemic therapy or best supportive care) with or without vascular endothelial growth factor inhibitors were included in the study. Outcomes reported included progression-free survival and overall survival. RESULTS A total of 4445 patients with liver metastases from 25 randomized controlled trials were included in this analysis. The addition of vascular endothelial growth factor inhibitors to standard systemic therapy or best supportive care was associated with superior progression-free survival (HR = 0.49; 95% CI, 0.40-0.61) and overall survival (HR = 0.83; 95% CI, 0.74-0.93) in patients with liver metastases. In a subgroup analysis of patients with versus patients without liver metastases, the benefit with vascular endothelial growth factor inhibitors was more pronounced in the group with liver metastases (HR = 0.44) versus without (HR = 0.57) for progression-free survival, but not for overall survival. CONCLUSION The addition of vascular endothelial growth factor inhibitors to standard management improved survival outcomes in patients with liver metastasis across cancers.
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Affiliation(s)
- Jordan W. Conway
- Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2065, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2050, Australia
| | - Jorja Braden
- Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2065, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2050, Australia
| | - Serigne N. Lo
- Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2065, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Richard A. Scolyer
- Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2065, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2050, Australia
- Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
- NSW Health Pathology, Sydney, NSW 2099, Australia
| | - Matteo S. Carlino
- Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2065, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, NSW 2148, Australia
| | - Alexander M. Menzies
- Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2065, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Royal North Shore Hospital, Sydney, NSW 2065, Australia
- Mater Hospital, Sydney, NSW 2060, Australia
| | - Georgina V. Long
- Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2065, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2050, Australia
- Royal North Shore Hospital, Sydney, NSW 2065, Australia
- Mater Hospital, Sydney, NSW 2060, Australia
| | - Ines Pires da Silva
- Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2065, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2050, Australia
- Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, NSW 2148, Australia
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5
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Silla L. Peripheral blood persistence and expansion of transferred non-genetically modified Natural Killer cells might not be necessary for clinical activity. IMMUNOTHERAPY ADVANCES 2023; 3:ltac024. [PMID: 36726770 PMCID: PMC9885937 DOI: 10.1093/immadv/ltac024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 01/12/2023] [Indexed: 01/15/2023] Open
Abstract
Natural killer (NK) cells are innate lymphocytes that react without previous exposition to virus infected or malignant cells and stimulate adaptive immune response to build a long-lasting immunity against it. To that end, tissue resident NK cells are predominantly regulatory as opposed to cytotoxic. In the hematopoietic stem cell transplant (HSCT) setting, which curative potential relies on the graft versus leukemia effect, NK cells are known to play a significant role. This knowledge has paved the way to the active investigation on its anti-tumor effect outside the stem cell transplant scenario. Based on the relevant literature on the adoptive transfer of non-genetically modified NK cells for the treatment of relapsed/refractory acute leukemia and on our own experience, we discuss the role of donor cell peripheral blood persistence and expansion and its lack of correlation with anti-leukemia activity.
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Affiliation(s)
- Lucia Silla
- Correspondence: Rua Ramiro, Barcelos #2350, Universidade Federal do Rio, Grande do Sul, Porto Alegre, RS 90035-903, Brazil;
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6
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Gama JFG, Cardoso LMDF, Bisaggio RDC, Lagrota-Candido J, Henriques-Pons A, Alves LA. Immunological Tolerance in Liver Transplant Recipients: Putative Involvement of Neuroendocrine-Immune Interactions. Cells 2022; 11:cells11152327. [PMID: 35954171 PMCID: PMC9367574 DOI: 10.3390/cells11152327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 06/20/2022] [Accepted: 06/29/2022] [Indexed: 02/04/2023] Open
Abstract
The transplantation world changed significantly following the introduction of immunosuppressants, with millions of people saved. Several physicians have noted that liver recipients that do not take their medication for different reasons became tolerant regarding kidney, heart, and lung transplantations at higher frequencies. Most studies have attempted to explain this phenomenon through unique immunological mechanisms and the fact that the hepatic environment is continuously exposed to high levels of pathogen-associated molecular patterns (PAMPs) or non-pathogenic microorganism-associated molecular patterns (MAMPs) from commensal flora. These components are highly inflammatory in the periphery but tolerated in the liver as part of the normal components that arrive via the hepatic portal vein. These immunological mechanisms are discussed herein based on current evidence, although we hypothesize the participation of neuroendocrine-immune pathways, which have played a relevant role in autoimmune diseases. Cells found in the liver present receptors for several cytokines, hormones, peptides, and neurotransmitters that would allow for system crosstalk. Furthermore, the liver is innervated by the autonomic system and may, thus, be influenced by the parasympathetic and sympathetic systems. This review therefore seeks to discuss classical immunological hepatic tolerance mechanisms and hypothesizes the possible participation of the neuroendocrine-immune system based on the current literature.
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Affiliation(s)
- Jaciara Fernanda Gomes Gama
- Laboratory of Cellular Communication, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Brazil Avenue, 4365-Manguinhos, Rio de Janeiro 21045-900, Brazil; (J.F.G.G.); (L.M.d.F.C.)
- Laboratory of Immunopathology, Department of Immunobiology, Biology Institute, Federal Fluminense University (UFF), Gragoatá Bl-M Campus, Niterói 24210-200, Brazil;
| | - Liana Monteiro da Fonseca Cardoso
- Laboratory of Cellular Communication, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Brazil Avenue, 4365-Manguinhos, Rio de Janeiro 21045-900, Brazil; (J.F.G.G.); (L.M.d.F.C.)
| | - Rodrigo da Cunha Bisaggio
- Department of Biotechnology, Federal Institute of Rio de Janeiro (IFRJ), Maracanã, Rio de Janeiro 20270-021, Brazil;
| | - Jussara Lagrota-Candido
- Laboratory of Immunopathology, Department of Immunobiology, Biology Institute, Federal Fluminense University (UFF), Gragoatá Bl-M Campus, Niterói 24210-200, Brazil;
| | - Andrea Henriques-Pons
- Laboratory of Innovations in Therapies, Education, and Bioproducts, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21041-361, Brazil;
| | - Luiz A. Alves
- Laboratory of Cellular Communication, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Brazil Avenue, 4365-Manguinhos, Rio de Janeiro 21045-900, Brazil; (J.F.G.G.); (L.M.d.F.C.)
- Correspondence: or ; Tel.: +55-(21)-2562-1816 (ext. 1841)
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7
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Lee JC, Green MD, Huppert LA, Chow C, Pierce RH, Daud AI. The Liver-Immunity Nexus and Cancer Immunotherapy. Clin Cancer Res 2022; 28:5-12. [PMID: 34285059 PMCID: PMC8897983 DOI: 10.1158/1078-0432.ccr-21-1193] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/24/2021] [Accepted: 07/16/2021] [Indexed: 01/03/2023]
Abstract
The impact of liver metastases on immune checkpoint-inhibitor effectiveness in patients with solid-tumor malignancies has been the focus of several recent clinical and translational studies. We review the literature describing the immune functions of the liver and particularly the mechanistic observations in these studies. The initial clinical observation was that pembrolizumab appeared to be much less effective in melanoma and non-small cell lung cancer (NSCLC) patients with liver metastasis. Subsequently other clinical studies have extended and reported similar findings with programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitors in many cancers. Two recent translational studies in animal models have dissected the mechanism of this systemic immune suppression. In both studies CD11b+ suppressive macrophages generated by liver metastasis in a two-site MC38 model appear to delete CD8+ T cells in a FasL-dependent manner. In addition, regulatory T-cell (Treg) activation was observed and contributed to the distal immunosuppression. Finally, we discuss some of the interventions reported to address liver immune suppression, such as radiation therapy, combination checkpoint blockade, and Treg depletion.
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Affiliation(s)
- James C. Lee
- Divisions of Hematology and Medical Oncology, Department of
Medicine, University of California San Francisco, San Francisco, California.,Parker Institute for Cancer Immunotherapy, San Francisco,
California
| | - Michael D. Green
- Department of Radiation Oncology, Michigan Medicine,
University of Michigan, Ann Arbor, Michigan.,Veterans Affairs Ann Arbor Healthcare System, U.S.
Department of Veterans Affairs, Ann Arbor, Michigan
| | - Laura A. Huppert
- Divisions of Hematology and Medical Oncology, Department of
Medicine, University of California San Francisco, San Francisco, California
| | - Christine Chow
- Divisions of Hematology and Medical Oncology, Department of
Medicine, University of California San Francisco, San Francisco, California
| | | | - Adil I. Daud
- Divisions of Hematology and Medical Oncology, Department of
Medicine, University of California San Francisco, San Francisco, California.,Parker Institute for Cancer Immunotherapy, San Francisco,
California
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8
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Vacani-Martins N, Meuser-Batista M, dos Santos CDLP, Hasslocher-Moreno AM, Henriques-Pons A. The Liver and the Hepatic Immune Response in Trypanosoma cruzi Infection, a Historical and Updated View. Pathogens 2021; 10:pathogens10091074. [PMID: 34578107 PMCID: PMC8465576 DOI: 10.3390/pathogens10091074] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/05/2021] [Accepted: 08/11/2021] [Indexed: 12/12/2022] Open
Abstract
Chagas disease was described more than a century ago and, despite great efforts to understand the underlying mechanisms that lead to cardiac and digestive manifestations in chronic patients, much remains to be clarified. The disease is found beyond Latin America, including Japan, the USA, France, Spain, and Australia, and is caused by the protozoan Trypanosoma cruzi. Dr. Carlos Chagas described Chagas disease in 1909 in Brazil, and hepatomegaly was among the clinical signs observed. Currently, hepatomegaly is cited in most papers published which either study acutely infected patients or experimental models, and we know that the parasite can infect multiple cell types in the liver, especially Kupffer cells and dendritic cells. Moreover, liver damage is more pronounced in cases of oral infection, which is mainly found in the Amazon region. However, the importance of liver involvement, including the hepatic immune response, in disease progression does not receive much attention. In this review, we present the very first paper published approaching the liver's participation in the infection, as well as subsequent papers published in the last century, up to and including our recently published results. We propose that, after infection, activated peripheral T lymphocytes reach the liver and induce a shift to a pro-inflammatory ambient environment. Thus, there is an immunological integration and cooperation between peripheral and hepatic immunity, contributing to disease control.
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Affiliation(s)
- Natalia Vacani-Martins
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21041-361, Brazil; (N.V.-M.); (C.d.L.P.d.S.)
| | - Marcelo Meuser-Batista
- Depto de Anatomia Patológica e Citopatologia, Instituto Fernandes Figueira, Fundação Oswaldo Cruz, Rio de Janeiro 22250-020, Brazil;
| | - Carina de Lima Pereira dos Santos
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21041-361, Brazil; (N.V.-M.); (C.d.L.P.d.S.)
| | | | - Andrea Henriques-Pons
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21041-361, Brazil; (N.V.-M.); (C.d.L.P.d.S.)
- Correspondence:
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9
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Jacobs B, Gebel V, Heger L, Grèze V, Schild H, Dudziak D, Ullrich E. Characterization and Manipulation of the Crosstalk Between Dendritic and Natural Killer Cells Within the Tumor Microenvironment. Front Immunol 2021; 12:670540. [PMID: 34054844 PMCID: PMC8160470 DOI: 10.3389/fimmu.2021.670540] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 04/19/2021] [Indexed: 01/22/2023] Open
Abstract
Cellular therapy has entered the daily clinical life with the approval of CAR T cell therapeutics and dendritic cell (DCs) vaccines in the US and the EU. In addition, numerous other adoptive cellular products, including natural killer (NK) cells, are currently evaluated in early phase I/ II clinical trials for the treatment of cancer patients. Despite these promising accomplishments, various challenges remain to be mastered in order to ensure sustained therapeutic success. These include the identification of strategies by which tumor cells escape the immune system or establish an immunosuppressive tumor microenvironment (TME). As part of the innate immune system, DCs and NK cells are both present within the TME of various tumor entities. While NK cells are well known for their intrinsic anti-tumor activity by their cytotoxicity capacities and the secretion of pro-inflammatory cytokines, the role of DCs within the TME is a double-edged sword as different DC subsets have been described with either tumor-promoting or -inhibiting characteristics. In this review, we will discuss recent findings on the interaction of DCs and NK cells under physiological conditions and within the TME. One focus is the crosstalk of various DC subsets with NK cells and their impact on the progression or inhibition of tumor growth. In addition, we will provide suggestions to overcome the immunosuppressive outcome of the interaction of DCs and NK cells within the TME.
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Affiliation(s)
- Benedikt Jacobs
- Department of Internal Medicine 5, Haematology and Oncology, Friedrich Alexander University Erlangen-Nuremberg (FAU), University Hospital Erlangen, Erlangen, Germany
| | - Veronika Gebel
- Children's Hospital, Goethe-University Frankfurt, Frankfurt, Germany.,Experimental Immunology, Goethe University Frankfurt , Frankfurt, Germany.,Frankfurt Cancer Institute, Goethe University, Frankfurt, Germany
| | - Lukas Heger
- Department of Dermatology, Laboratory of Dendritic Cell Biology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Victoria Grèze
- Children's Hospital, Goethe-University Frankfurt, Frankfurt, Germany.,Experimental Immunology, Goethe University Frankfurt , Frankfurt, Germany.,Frankfurt Cancer Institute, Goethe University, Frankfurt, Germany
| | - Hansjörg Schild
- Institute of Immunology, University Medical Center Mainz, Mainz, Germany.,Research Centre for Immunotherapy, University Medical Center Mainz, Mainz, Germany
| | - Diana Dudziak
- Department of Dermatology, Laboratory of Dendritic Cell Biology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Evelyn Ullrich
- Children's Hospital, Goethe-University Frankfurt, Frankfurt, Germany.,Experimental Immunology, Goethe University Frankfurt , Frankfurt, Germany.,Frankfurt Cancer Institute, Goethe University, Frankfurt, Germany
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10
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Natural Killer-Dendritic Cell Interactions in Liver Cancer: Implications for Immunotherapy. Cancers (Basel) 2021; 13:cancers13092184. [PMID: 34062821 PMCID: PMC8124166 DOI: 10.3390/cancers13092184] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/22/2021] [Accepted: 04/29/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The reciprocal crosstalk between dendritic cells (DCs) and natural killer (NK) cells plays a pivotal role in regulating immune defense against viruses and tumors. The Th-cell polarizing ability, cytokine-producing capacity, chemokine expression, and migration of DCs are regulated by activated NK cells. Conversely, the effector functions including lysis and cytokine production, proliferation, and migration of NK cells are influenced by close interactions with activated DCs. In this review, we explore the impact of DC–NK cell crosstalk and its therapeutic potential in immune control of liver malignances. Abstract Natural killer (NK) and dendritic cells (DCs) are innate immune cells that play a crucial role in anti-tumor immunity. NK cells kill tumor cells through direct cytotoxicity and cytokine secretion. DCs are needed for the activation of adaptive immune responses against tumor cells. Both NK cells and DCs are subdivided in several subsets endowed with specialized effector functions. Crosstalk between NK cells and DCs leads to the reciprocal control of their activation and polarization of immune responses. In this review, we describe the role of NK cells and DCs in liver cancer, focusing on the mechanisms involved in their reciprocal control and activation. In this context, intrahepatic NK cells and DCs present unique immunological features, due to the constant exposure to non-self-circulating antigens. These interactions might play a fundamental role in the pathology of primary liver cancer, namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Additionally, the implications of these immune changes are relevant from the perspective of improving the cancer immunotherapy strategies in HCC and ICC patients.
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11
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Perera Molligoda Arachchige AS. Human NK cells: From development to effector functions. Innate Immun 2021; 27:212-229. [PMID: 33761782 PMCID: PMC8054151 DOI: 10.1177/17534259211001512] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 02/19/2021] [Indexed: 12/11/2022] Open
Abstract
NK cells are the major lymphocyte subset of the innate immune system that mediates antiviral and anti-tumor responses. It is well established that they develop mechanisms to distinguish self from non-self during the process of NK cell education. Unlike T and B cells, natural killer cells lack clonotypic receptors and are activated after recognizing their target via germline-encoded receptors through natural cytotoxicity, cytokine stimulation, and Ab-dependent cellular cytotoxicity. Subsequently, they utilize cytotoxic granules, death receptor ligands, and cytokines to perform their effector functions. In this review, we provide a general overview of human NK cells, as opposed to murine NK cells, discussing their ontogeny, maturation, receptor diversity, types of responses, and effector functions. Furthermore, we also describe recent advances in human NK cell biology, including tissue-resident NK cell populations, NK cell memory, and novel approaches used to target NK cells in cancer immunotherapy.
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12
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Jameson G, Robinson MW. Insights Into Human Intrahepatic NK Cell Function From Single Cell RNA Sequencing Datasets. Front Immunol 2021; 12:649311. [PMID: 33828559 PMCID: PMC8019706 DOI: 10.3389/fimmu.2021.649311] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 02/22/2021] [Indexed: 12/13/2022] Open
Abstract
Diverse populations of natural killer (NK) cells have been identified in circulating peripheral blood and a wide variety of different tissues and organs. These tissue-resident NK cell populations are phenotypically distinct from circulating NK cells, however, functional descriptions of their roles within tissues are lacking. Recent advances in single cell RNA sequencing (scRNA-seq) have enabled detailed transcriptional profiling of tissues at the level of single cells and provide the opportunity to explore NK cell diversity within tissues. This review explores potential novel functions of human liver-resident (lr)NK cells identified in human liver scRNA-seq studies. By comparing these datasets we identified up-regulated and down-regulated genes associated with lrNK cells clusters. These genes encode a number of activating and inhibiting receptors, as well as signal transduction molecules, which highlight potential unique pathways that lrNK cells utilize to respond to stimuli within the human liver. This unique receptor repertoire of lrNK cells may confer the ability to regulate a number of immune cell populations, such as circulating monocytes and T cells, while avoiding activation by liver hepatocytes and Kupffer cells. Validating the expression of these receptors on lrNK cells and the proposed cellular interactions within the human liver will expand our understanding of the liver-specific homeostatic roles of this tissue-resident immune cell population.
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Affiliation(s)
- Gráinne Jameson
- School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Mark W Robinson
- Department of Biology, Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland
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13
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Polidoro MA, Mikulak J, Cazzetta V, Lleo A, Mavilio D, Torzilli G, Donadon M. Tumor microenvironment in primary liver tumors: A challenging role of natural killer cells. World J Gastroenterol 2020; 26:4900-4918. [PMID: 32952338 PMCID: PMC7476172 DOI: 10.3748/wjg.v26.i33.4900] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/24/2020] [Accepted: 08/19/2020] [Indexed: 02/06/2023] Open
Abstract
In the last years, several studies have been focused on elucidate the role of tumor microenvironment (TME) in cancer development and progression. Within TME, cells from adaptive and innate immune system are one of the main abundant components. The dynamic interactions between immune and cancer cells lead to the activation of complex molecular mechanisms that sustain tumor growth. This important cross-talk has been elucidate for several kind of tumors and occurs also in patients with liver cancer, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Liver is well-known to be an important immunological organ with unique microenvironment. Here, in normal conditions, the rich immune-infiltrating cells cooperate with non-parenchymal cells, such as liver sinusoidal endothelial cells and Kupffer cells, favoring self-tolerance against gut antigens. The presence of underling liver immunosuppressive microenvironment highlights the importance to dissect the interaction between HCC and iCCA cells with immune infiltrating cells, in order to understand how this cross-talk promotes tumor growth. Deeper attention is, in fact, focused on immune-based therapy for these tumors, as promising approach to counteract the intrinsic anti-tumor activity of this microenvironment. In this review, we will examine the key pathways underlying TME cell-cell communications, with deeper focus on the role of natural killer cells in primary liver tumors, such as HCC and iCCA, as new opportunities for immune-based therapeutic strategies.
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Affiliation(s)
- Michela Anna Polidoro
- Hepatobiliary Immunopathology Laboratory, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
| | - Joanna Mikulak
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Rozzano 20089, Milan, Italy
| | - Valentina Cazzetta
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
| | - Ana Lleo
- Hepatobiliary Immunopathology Laboratory, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Internal Medicine, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
| | - Domenico Mavilio
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Rozzano 20089, Milan, Italy
| | - Guido Torzilli
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
| | - Matteo Donadon
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
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14
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Cong J. Metabolism of Natural Killer Cells and Other Innate Lymphoid Cells. Front Immunol 2020; 11:1989. [PMID: 32983138 PMCID: PMC7484708 DOI: 10.3389/fimmu.2020.01989] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 07/23/2020] [Indexed: 12/15/2022] Open
Abstract
Natural killer (NK) cells are the host's first line of defense against tumors and viral infections without prior sensitization. It is increasingly accepted that NK cells belong to the innate lymphoid cell (ILC) family. Other ILCs, comprising ILC1s, ILC2s, ILC3s and lymphoid tissue inducer (LTi) cells, are largely non-cytotoxic, tissue-resident cells, which function to protect local microenvironments against tissue insults and maintain homeostasis. Recently, evidence has accumulated that metabolism supports many aspects of the biology of NK cells and other ILCs, and that metabolic reprogramming regulates their development and function. Here, we outline the current understanding of ILC metabolism, and describe how metabolic processes are affected, and how metabolic defects are coupled to dysfunction of ILCs, in disease settings. Furthermore, we summarize the current and potential directions for immunotherapy involving targeting of ILC metabolism. Finally, we discuss the open questions in the rapidly expanding field of ILC metabolism.
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Affiliation(s)
- Jingjing Cong
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, China
- Institue of Immunology, University of Science and Technology of China, Hefei, China
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15
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Prevention of liver metastases through perioperative acute CpG-C immune stimulation. Cancer Immunol Immunother 2020; 69:2021-2031. [PMID: 32405793 DOI: 10.1007/s00262-020-02596-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Accepted: 04/27/2020] [Indexed: 12/21/2022]
Abstract
Following excision of colorectal tumors, metastatic disease is prevalent, primarily occurs in the liver, and is highly predictive of poor prognosis. The perioperative period is now recognized as critical in determining the incidence of postoperative metastases and long-term cancer outcomes. Thus, various perioperative prophylactic interventions are currently studied during this time frame. However, immune stimulation during the perioperative period has rarely been attempted due to specific contraindications to surgery and various adverse effects. Here, to prevent liver metastases, we perioperatively employed a TLR-9 agonist, CpG-C, which exhibits minimal pyrogenic and other adverse effects in patients. We found that marginating-hepatic (MH) cells in BALB/c mice contained high percentage of NK cells, but exhibited negligible NK cytotoxicity, as previously reported in humans. However, a single CpG-C administration (25-100 µg/mouse) doubled MH-NK cell numbers, increased NK cell activation and maturation markers (NKp46, CD11b), decreased the inhibitory NKG2A ligand, and dramatically increased MH-NK-cell cytotoxicity against the syngeneic CT26 colon cancer line. Moreover, in operated mice, this innocuous intervention also markedly improved resistance to CT26 and MC38 hepatic metastases in BALB/c and C57BL/6 mice, respectively. Beneficial effects of CpG-C were mediated through activation of MH-NK cells, as indicated by an in vivo NK depletion study. Last, CpG-C protected against surgery-induced suppression of MH-NK cytotoxicity and improved their activation indices. Thus, we suggest that systemic perioperative CpG-C treatment should be considered and studied as a novel therapeutic approach to improve long-term cancer outcomes in colorectal cancer patients.
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16
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Poznanski SM, Ashkar AA. What Defines NK Cell Functional Fate: Phenotype or Metabolism? Front Immunol 2019; 10:1414. [PMID: 31275330 PMCID: PMC6593107 DOI: 10.3389/fimmu.2019.01414] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 06/04/2019] [Indexed: 01/03/2023] Open
Abstract
NK cells are capable of an array of functions that range widely from their classic anti-tumor and anti-viral cytotoxic effector functions, to their critical regulatory roles in controlling inflammatory immune responses and promoting tissue growth. However, the mechanisms that polarize NK cells to these distinct and opposing functions are incompletely understood. NK cell functional subsets are primarily identified and studied based on phenotype, which has served as an accessible means for profiling NK cells and does offer information on NK cell activation state. However, inconsistencies have emerged in using classic phenotypes to inform function, which raise the questions: Can phenotype in fact define NK cell functional fate? What factors do profile and drive NK cell fate? In other immune cells, cell metabolism has been shown to critically determine subset polarization. There is a growing body of evidence that cell metabolism is integral to NK cell effector functions. Glucose-driven glycolysis and oxidative metabolism have been shown to drive classic NK cell anti-tumor and anti-viral effector functions. Recent studies have uncovered a critical role for metabolism in NK cell development, education, and memory generation. In this review, we will draw on the evidence to date to investigate the relationship between NK cell phenotype, metabolism, and functional fate. We explore a paradigm in which the differential activity of metabolic pathways within NK cells produce distinct metabolic fingerprints that comprehensively distinguish and drive the range of NK cell functional abilities. We will discuss future areas of study that are needed to develop and test this paradigm and suggest strategies to efficiently profile NK cells based on metabolism. Given the emerging role of metabolism in driving NK cell fates, profiling and modulating NK cell metabolism holds profound therapeutic potential to tune inflammatory and regulatory NK cell responses to treat disease.
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Affiliation(s)
- Sophie M Poznanski
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
| | - Ali A Ashkar
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
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17
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Expression of costimulatory and inhibitory receptors in FoxP3 + regulatory T cells within the tumor microenvironment: Implications for combination immunotherapy approaches. Adv Cancer Res 2019; 144:193-261. [PMID: 31349899 DOI: 10.1016/bs.acr.2019.05.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The unprecedented success of immune checkpoint inhibitors has given rise to a rapidly growing number of immuno-oncology agents undergoing preclinical and clinical development and an exponential increase in possible combinations. Defining a clear rationale for combinations by identifying synergies between immunomodulatory pathways has therefore become a high priority. Immunosuppressive regulatory T cells (Tregs) within the tumor microenvironment (TME) represent a major roadblock to endogenous and therapeutic tumor immunity. However, Tregs are also essential for the maintenance of immunological self-tolerance, and share many molecular pathways with conventional T cells including cytotoxic T cells, the primary mediators of tumor immunity. Hence the inability to specifically target and neutralize Tregs within the TME of cancer patients without globally compromising self-tolerance poses a significant challenge. Here we review recent advances in the characterization of tumor-infiltrating Tregs with a focus on costimulatory and inhibitory receptors. We discuss receptor expression patterns, their functional role in Treg biology and mechanistic insights gained from targeting these receptors in preclinical models to evaluate their potential as clinical targets. We further outline a framework of parameters that could be used to refine the assessment of Tregs in cancer patients and increase their value as predictive biomarkers. Finally, we propose modalities to integrate our increasing knowledge on Treg phenotype and function for the rational design of checkpoint inhibitor-based combination therapies. Such combinations have great potential for synergy, as they could concomitantly enhance cytotoxic T cells and inhibit Tregs within the TME, thereby increasing the efficacy of current cancer immunotherapies.
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18
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Mikulak J, Bruni E, Oriolo F, Di Vito C, Mavilio D. Hepatic Natural Killer Cells: Organ-Specific Sentinels of Liver Immune Homeostasis and Physiopathology. Front Immunol 2019; 10:946. [PMID: 31114585 PMCID: PMC6502999 DOI: 10.3389/fimmu.2019.00946] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 04/12/2019] [Indexed: 12/16/2022] Open
Abstract
The liver is considered a preferential tissue for NK cells residency. In humans, almost 50% of all intrahepatic lymphocytes are NK cells that are strongly imprinted in a liver-specific manner and show a broad spectrum of cellular heterogeneity. Hepatic NK (he-NK) cells play key roles in tuning liver immune response in both physiological and pathological conditions. Therefore, there is a pressing need to comprehensively characterize human he-NK cells to better understand the related mechanisms regulating their effector-functions within the dynamic balance between immune-tolerance and immune-surveillance. This is of particular relevance in the liver that is the only solid organ whose parenchyma is constantly challenged on daily basis by millions of foreign antigens drained from the gut. Therefore, the present review summarizes our current knowledge on he-NK cells in the light of the latest discoveries in the field of NK cell biology and clinical relevance.
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Affiliation(s)
- Joanna Mikulak
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Elena Bruni
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Ferdinando Oriolo
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Clara Di Vito
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy
| | - Domenico Mavilio
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
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19
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Huang H, Lu Y, Zhou T, Gu G, Xia Q. Innate Immune Cells in Immune Tolerance After Liver Transplantation. Front Immunol 2018; 9:2401. [PMID: 30473690 PMCID: PMC6237933 DOI: 10.3389/fimmu.2018.02401] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 09/27/2018] [Indexed: 12/13/2022] Open
Abstract
Currently, liver transplantation is the most effective treatment for end-stage liver disease. Immunosuppressive agents are required to be taken after the operations, which have significantly reduced rejection rates and improved the short-term (<1 year) survival rates. However, post-transplant complications related to the immunosuppressive therapy have led to the development of new protocols aimed at protecting renal function and preventing de novo cancer and dysmetabolic syndrome. Donor specific immune tolerance, which means the mature immune systems of recipients will not attack the grafts under the conditions without any immunosuppression therapies, is considered the optimal state after liver transplantation. There have been studies that have shown that some patients can reach this immune tolerance state after liver transplantation. The intrahepatic immune system is quite different from that in other solid organs, especially the innate immune system. It contains a variety of liver specific cells, such as liver-derived dendritic cells, Kupffer cells, liver sinusoidal endothelial cells, liver-derived natural killer (NK) cells, natural killer T (NKT) cells, and so on. Depending on their specific structures and functions, these intrahepatic innate immune cells play important roles in the development of intrahepatic immune tolerance. In this article, in order to have a deeper understanding of the tolerogenic functions of liver, we summarized the molecular mechanisms of immune tolerance induced by intrahepatic innate immune cells after liver transplantation.
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Affiliation(s)
- Hongting Huang
- Department of Hepatic Surgery and Liver Transplantation Center, School of Medicine, Renji Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Yefeng Lu
- Department of Hepatic Surgery and Liver Transplantation Center, School of Medicine, Renji Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Tao Zhou
- Department of Hepatic Surgery and Liver Transplantation Center, School of Medicine, Renji Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Guangxiang Gu
- Department of Hepatic Surgery and Liver Transplantation Center, School of Medicine, Renji Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Qiang Xia
- Department of Hepatic Surgery and Liver Transplantation Center, School of Medicine, Renji Hospital, Shanghai Jiaotong University, Shanghai, China
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20
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Shen Y, Li J, Wang SQ, Jiang W. Ambiguous roles of innate lymphoid cells in chronic development of liver diseases. World J Gastroenterol 2018; 24:1962-1977. [PMID: 29760540 PMCID: PMC5949710 DOI: 10.3748/wjg.v24.i18.1962] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 04/25/2018] [Accepted: 05/06/2018] [Indexed: 02/06/2023] Open
Abstract
Innate lymphoid cells (ILCs) are defined as a distinct arm of innate immunity. According to their profile of secreted cytokines and lineage-specific transcriptional factors, ILCs can be categorized into the following three groups: group 1 ILCs (including natural killer (NK) cells and ILC1s) are dependent on T-bet and can produce interferon-γ; group 2 ILCs (ILC2s) are dependent on GATA3 and can produce type 2 cytokines, including interleukin (IL)-5 and IL-13; and, group 3 ILCs (including lymphoid tissue-like cells and ILC3s) are dependent on RORγt and can produce IL-22 and IL-17. Collaborative with adaptive immunity, ILCs are highly reactive innate effectors that promptly orchestrate immunity, inflammation and tissue repair. Dysregulation of ILCs might result in inflammatory disorders. Evidence regarding the function of intrahepatic ILCs is emerging from longitudinal studies of inflammatory liver diseases wherein they exert both physiological and pathological functions, including immune homeostasis, defenses and surveillance. Their overall effect on the liver depends on the balance of their proinflammatory and antiinflammatory populations, specific microenvironment and stages of immune responses. Here, we review the current data about ILCs in chronic liver disease progression, to reveal their roles in different stages as well as to discuss their therapeutic potency as intervention targets.
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Affiliation(s)
- Yue Shen
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jing Li
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of Gastroenterology, Tongji Hospital, Tongji University, Shanghai 200000, China
| | - Si-Qi Wang
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Wei Jiang
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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21
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Zheng M, Sun H, Tian Z. Natural killer cells in liver diseases. Front Med 2018; 12:269-279. [PMID: 29675689 DOI: 10.1007/s11684-018-0621-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Accepted: 12/06/2017] [Indexed: 12/12/2022]
Abstract
The liver has been characterized as a frontline lymphoid organ with complex immunological features such as liver immunity and liver tolerance. Liver tolerance plays an important role in liver diseases including acute inflammation, chronic infection, autoimmune disease, and tumors. The liver contains a large proportion of natural killer (NK) cells, which exhibit heterogeneity in phenotypic and functional characteristics. NK cell activation, well known for its role in the immune surveillance against tumor and pathogen-infected cells, depends on the balance between numerous activating and inhibitory signals. In addition to the innate direct "killer" functions, NK cell activity contributes to regulate innate and adaptive immunity (helper or regulator). Under the setting of liver diseases, NK cells are of great importance for stimulating or inhibiting immune responses, leading to either immune activation or immune tolerance. Here, we focus on the relationship between NK cell biology, such as their phenotypic features and functional diversity, and liver diseases.
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Affiliation(s)
- Meijuan Zheng
- Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
| | - Haoyu Sun
- Institute of Immunology, Key Laboratory of Innate Immunity and Chronic Disease of Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, 230027, China
| | - Zhigang Tian
- Institute of Immunology, Key Laboratory of Innate Immunity and Chronic Disease of Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, 230027, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China
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22
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Peng H, Tian Z. Diversity of tissue-resident NK cells. Semin Immunol 2017; 31:3-10. [PMID: 28802693 DOI: 10.1016/j.smim.2017.07.006] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Accepted: 07/19/2017] [Indexed: 02/07/2023]
Abstract
Although natural killer (NK) cells were initially named for their spontaneous tumor-killing capacity, their concept has been greatly expanded with more than 40 years of extensive investigation. Currently, NK cells are known as a heterogeneous population of innate lymphoid cell (ILC) family, consisting of different subsets with unique phenotypic and functional features. Recent studies have shown that tissue-resident NK (trNK) cells, which are distinct from conventional NK (cNK) cells, preferentially distribute in non-lymphoid tissues, such as the liver, uterus, salivary gland, and adipose. In this review, we provide a comprehensive overview of the current knowledge about the phenotype, function and development of trNK cells across different tissues and describe the similarities and differences between diverse trNK cells and cNK cells, with a particular focus on the tissue-specific characteristics of different trNK cells.
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Affiliation(s)
- Hui Peng
- Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
| | - Zhigang Tian
- Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
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23
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Wu Y, Tian Z, Wei H. Developmental and Functional Control of Natural Killer Cells by Cytokines. Front Immunol 2017; 8:930. [PMID: 28824650 PMCID: PMC5543290 DOI: 10.3389/fimmu.2017.00930] [Citation(s) in RCA: 202] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 07/20/2017] [Indexed: 12/20/2022] Open
Abstract
Natural killer (NK) cells are effective in combating infections and tumors and as such are tempting for adoptive transfer therapy. However, they are not homogeneous but can be divided into three main subsets, including cytotoxic, tolerant, and regulatory NK cells, with disparate phenotypes and functions in diverse tissues. The development and functions of such NK cells are controlled by various cytokines, such as fms-like tyrosine kinase 3 ligand (FL), kit ligand (KL), interleukin (IL)-3, IL-10, IL-12, IL-18, transforming growth factor-β, and common-γ chain family cytokines, which operate at different stages by regulating distinct signaling pathways. Nevertheless, the specific roles of each cytokine that regulates NK cell development or that shapes different NK cell functions remain unclear. In this review, we attempt to describe the characteristics of each cytokine and the existing protocols to expand NK cells using different combinations of cytokines and feeder cells. A comprehensive understanding of the role of cytokines in NK cell development and function will aid the generation of better efficacy for adoptive NK cell treatment.
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Affiliation(s)
- Yang Wu
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China
| | - Zhigang Tian
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China.,Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, China
| | - Haiming Wei
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China.,Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, China
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24
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Hepatic stroma-educated regulatory DCs suppress CD8 + T cell proliferation in mice. Oncotarget 2017; 8:93414-93425. [PMID: 29212160 PMCID: PMC5706806 DOI: 10.18632/oncotarget.18459] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 05/22/2017] [Indexed: 02/07/2023] Open
Abstract
Liver dendritic cells (DCs) display immunosuppressive activities and inhibit the CD4+ T cell response. The present study assessed whether and how liver DCs suppress CD8+ T cells. We found that bone marrow-derived mature DCs incubated with liver stromal cells were characterized by a longer life span, reduced CD11c, IA/IE, CD80, CD86, and CD40 expression, and increased CD11b expression. These unique liver stromal cell-educated mature DCs (LSed-DCs) stimulated CD8+ T cells to express CD25 and CD69, but inhibited their proliferation. CD8+ T cell suppression depended on soluble factors released by LSed-DCs, but not cell-cell contact. Compared with mature DCs, LSed-DCs produced more nitric oxide and IL-10. Addition of a nitric oxide synthase inhibitor, PBIT, but not an IL-10-blocking mAb, reversed LSed-DC inhibition of CD8+ T cell proliferation. We also found that LSed-DCs reduced CD8+ T cell-mediated liver damage in a mouse model of autoimmune hepatitis. These results demonstrate that the liver stroma induces mature DCs to differentiate into regulatory DCs that suppress CD8+ T cell proliferation, and thus contribute to liver tolerance.
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25
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Wagner B, da Silva Nardi F, Schramm S, Kraemer T, Celik AA, Dürig J, Horn PA, Dührsen U, Nückel H, Rebmann V. HLA-E allelic genotype correlates with HLA-E plasma levels and predicts early progression in chronic lymphocytic leukemia. Cancer 2017; 123:814-823. [PMID: 27859015 DOI: 10.1002/cncr.30427] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 09/05/2016] [Accepted: 10/03/2016] [Indexed: 01/31/2023]
Abstract
BACKGROUND Human leukocyte antigen-E (HLA-E) is a nonclassical major histocompatibility complex class I molecule that recently came into sharper focus as a putative marker of advanced tumor stages and disease progression. In solid tumors, increased HLA-E expression as well as elevated soluble HLA-E (sHLA-E) plasma levels are associated with a poor prognosis; however, a role for HLA-E in hematologic malignancies remains to be established. METHODS The authors analyzed HLA-E alleles and sHLA-E levels in a cohort of 110 individuals with chronic lymphocytic leukemia (CLL). RESULTS In patients with CLL, levels of sHLA-E increased with advanced disease stage (P = .01) and decreased after therapy (P = .01). Longitudinal follow-up revealed that both HLA-E*01:03 alleles and high levels of sHLA-E were significantly associated with a requirement for early treatment in patients with CLL (P = .027 and P = .023, respectively). In vitro, sHLA-E inhibited degranulation and interferon-γ production by natural killer (NK) cells when cocultivated with tumor cells. Moreover, sHLA-E loaded onto microspheres induced transforming growth factor-β release by NK cells. Multivariate analysis revealed that the presence of at least 1 HLA-E*01:03 allele was an independent predictor of a requirement for early treatment. CONCLUSIONS HLA-E alleles and sHLA-E levels may represent novel biomarkers for early disease progression in patients with CLL. Cancer 2017;123:814-23. © 2016 American Cancer Society.
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MESH Headings
- Aged
- Alleles
- Biomarkers, Tumor/blood
- Disease Progression
- Female
- Genotype
- Histocompatibility Antigens Class I/blood
- Histocompatibility Antigens Class I/genetics
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/blood
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Leukocytes/pathology
- Male
- Middle Aged
- Prognosis
- HLA-E Antigens
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Affiliation(s)
- Bettina Wagner
- Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany
| | - Fabiola da Silva Nardi
- Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany
- Coordinaton for the Improvement of Higher Education Personnel (CAPES) Foundation, Ministry of Education of Brazil, Brasilia, Brazil
| | - Sabine Schramm
- Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany
| | - Thomas Kraemer
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Alexander A Celik
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Jan Dürig
- Department of Hematology, University Hospital Essen, Essen, Germany
| | - Peter A Horn
- Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany
| | - Ulrich Dührsen
- Department of Hematology, University Hospital Essen, Essen, Germany
| | - Holger Nückel
- Department of Hematology, University Hospital Essen, Essen, Germany
| | - Vera Rebmann
- Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany
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26
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Brown DL. Immunopathology of the Hepatobiliary System. MOLECULAR AND INTEGRATIVE TOXICOLOGY 2017:329-417. [DOI: 10.1007/978-3-319-47385-7_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Tripathi D, Venkatasubramanian S, Cheekatla SS, Paidipally P, Welch E, Tvinnereim AR, Vankayalapati R. A TLR9 agonist promotes IL-22-dependent pancreatic islet allograft survival in type 1 diabetic mice. Nat Commun 2016; 7:13896. [PMID: 27982034 PMCID: PMC5171644 DOI: 10.1038/ncomms13896] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 11/08/2016] [Indexed: 12/20/2022] Open
Abstract
Pancreatic islet transplantation is a promising potential cure for type 1 diabetes (T1D). Islet allografts can survive long term in the liver parenchyma. Here we show that liver NK1.1+ cells induce allograft tolerance in a T1D mouse model. The tolerogenic effects of NK1.1+ cells are mediated through IL-22 production, which enhances allograft survival and increases insulin secretion. Increased expression of NKG2A by liver NK1.1+ cells in islet allograft-transplanted mice is involved in the production of IL-22 and in the reduced inflammatory response to allografts. Vaccination of T1D mice with a CpG oligonucleotide TLR9 agonist (ODN 1585) enhances expansion of IL-22-producing CD3-NK1.1+ cells in the liver and prolongs allograft survival. Our study identifies a role for liver NK1.1+ cells, IL-22 and CpG oligonucleotides in the induction of tolerance to islet allografts in the liver parenchyma.
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Affiliation(s)
- Deepak Tripathi
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas 75708, USA
| | - Sambasivan Venkatasubramanian
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas 75708, USA
| | - Satyanarayana S. Cheekatla
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas 75708, USA
| | - Padmaja Paidipally
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas 75708, USA
| | - Elwyn Welch
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas 75708, USA
| | - Amy R. Tvinnereim
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas 75708, USA
| | - Ramakrishna Vankayalapati
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas 75708, USA
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28
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Immunosuppression in liver tumors: opening the portal to effective immunotherapy. Cancer Gene Ther 2016; 24:114-120. [DOI: 10.1038/cgt.2016.54] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 09/01/2016] [Indexed: 12/11/2022]
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29
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Horst AK, Neumann K, Diehl L, Tiegs G. Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells. Cell Mol Immunol 2016; 13:277-92. [PMID: 27041638 PMCID: PMC4856800 DOI: 10.1038/cmi.2015.112] [Citation(s) in RCA: 184] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 12/18/2015] [Accepted: 12/18/2015] [Indexed: 12/11/2022] Open
Abstract
The liver is a tolerogenic organ with exquisite mechanisms of immune regulation that ensure upkeep of local and systemic immune tolerance to self and foreign antigens, but that is also able to mount effective immune responses against pathogens. The immune privilege of liver allografts was recognized first in pigs in spite of major histo-compatibility complex mismatch, and termed the "liver tolerance effect". Furthermore, liver transplants are spontaneously accepted with only low-dose immunosuppression, and induce tolerance for non-hepatic co-transplanted allografts of the same donor. Although this immunotolerogenic environment is favorable in the setting of organ transplantation, it is detrimental in chronic infectious liver diseases like hepatitis B or C, malaria, schistosomiasis or tumorigenesis, leading to pathogen persistence and weak anti-tumor effects. The liver is a primary site of T-cell activation, but it elicits poor or incomplete activation of T cells, leading to their abortive activation, exhaustion, suppression of their effector function and early death. This is exploited by pathogens and can impair pathogen control and clearance or allow tumor growth. Hepatic priming of T cells is mediated by a number of local conventional and nonconventional antigen-presenting cells (APCs), which promote tolerance by immune deviation, induction of T-cell anergy or apoptosis, and generating and expanding regulatory T cells. This review will focus on the communication between classical and nonclassical APCs and lymphocytes in the liver in tolerance induction and will discuss recent insights into the role of innate lymphocytes in this process.
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Affiliation(s)
- Andrea Kristina Horst
- Institute of Experimental Immunology and Hepatology Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg D-20246, Germany
| | - Katrin Neumann
- Institute of Experimental Immunology and Hepatology Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg D-20246, Germany
| | - Linda Diehl
- Institute of Experimental Immunology and Hepatology Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg D-20246, Germany
| | - Gisa Tiegs
- Institute of Experimental Immunology and Hepatology Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg D-20246, Germany
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Peng H, Wisse E, Tian Z. Liver natural killer cells: subsets and roles in liver immunity. Cell Mol Immunol 2016; 13:328-36. [PMID: 26639736 PMCID: PMC4856807 DOI: 10.1038/cmi.2015.96] [Citation(s) in RCA: 127] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 10/14/2015] [Accepted: 10/19/2015] [Indexed: 12/11/2022] Open
Abstract
The liver represents a frontline immune organ that is constantly exposed to a variety of gut-derived antigens as a result of its unique location and blood supply. With a predominant role in innate immunity, the liver is enriched with various innate immune cells, among which natural killer (NK) cells play important roles in host defense and in maintaining immune balance. Hepatic NK cells were first described as 'pit cells' in the rat liver in the 1970s. Recent studies of NK cells in mouse and human livers have shown that two distinct NK cell subsets, liver-resident NK cells and conventional NK (cNK) cells, are present in this organ. Here, we review liver NK cell subsets in different species, revisiting rat hepatic pit cells and highlighting recent progress related to resident NK cells in mouse and human livers, and also discuss the dual roles of NK cells in liver immunity.
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Affiliation(s)
- Hui Peng
- Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Eddie Wisse
- Maastricht Multimodal Molecular Imaging Institute, Division of Nanoscopy, Universiteitssingel 50, Maastricht, The Netherlands
| | - Zhigang Tian
- Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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31
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Bayard C, Lepetitcorps H, Roux A, Larsen M, Fastenackels S, Salle V, Vieillard V, Marchant A, Stern M, Boddaert J, Bajolle F, Appay V, Sauce D. Coordinated expansion of both memory T cells and NK cells in response to CMV infection in humans. Eur J Immunol 2016; 46:1168-79. [DOI: 10.1002/eji.201546179] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 12/28/2015] [Accepted: 02/17/2016] [Indexed: 12/18/2022]
Affiliation(s)
- Charles Bayard
- Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris); Sorbonne Universités; DHU FAST, CR7, UPMC Univ Paris 06 Paris France
- INSERM, U1135; CIMI-Paris; Paris France
| | - Hélène Lepetitcorps
- Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris); Sorbonne Universités; DHU FAST, CR7, UPMC Univ Paris 06 Paris France
- INSERM, U1135; CIMI-Paris; Paris France
| | - Antoine Roux
- Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris); Sorbonne Universités; DHU FAST, CR7, UPMC Univ Paris 06 Paris France
- INSERM, U1135; CIMI-Paris; Paris France
- AP-HP, Service de pneumologie; Hôpital Foch; Suresnes France
| | - Martin Larsen
- Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris); Sorbonne Universités; DHU FAST, CR7, UPMC Univ Paris 06 Paris France
- INSERM, U1135; CIMI-Paris; Paris France
| | - Solène Fastenackels
- Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris); Sorbonne Universités; DHU FAST, CR7, UPMC Univ Paris 06 Paris France
- INSERM, U1135; CIMI-Paris; Paris France
| | - Virginie Salle
- AP-HP; Unité Médico-Chirurgicale de Cardiologie Congénitale et Pédiatrique/ M3C; Hôpital Necker enfants malades; Paris France
| | - Vincent Vieillard
- Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris); Sorbonne Universités; DHU FAST, CR7, UPMC Univ Paris 06 Paris France
- INSERM, U1135; CIMI-Paris; Paris France
| | - Arnaud Marchant
- Institute for Medical Immunology; Université Libre de Bruxelles; Charleroi Belgium
| | - Marc Stern
- AP-HP, Service de pneumologie; Hôpital Foch; Suresnes France
| | - Jacques Boddaert
- AP-HP; Service de gériatrie; Hôpital Pitié-Salpêtrière; Paris France
| | - Fanny Bajolle
- AP-HP; Unité Médico-Chirurgicale de Cardiologie Congénitale et Pédiatrique/ M3C; Hôpital Necker enfants malades; Paris France
| | - Victor Appay
- Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris); Sorbonne Universités; DHU FAST, CR7, UPMC Univ Paris 06 Paris France
- INSERM, U1135; CIMI-Paris; Paris France
| | - Delphine Sauce
- Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris); Sorbonne Universités; DHU FAST, CR7, UPMC Univ Paris 06 Paris France
- INSERM, U1135; CIMI-Paris; Paris France
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32
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Zimmermann HW, Bruns T, Weston CJ, Curbishley SM, Liaskou E, Li KK, Resheq YJ, Badenhorst PW, Adams DH. Bidirectional transendothelial migration of monocytes across hepatic sinusoidal endothelium shapes monocyte differentiation and regulates the balance between immunity and tolerance in liver. Hepatology 2016; 63:233-46. [PMID: 26473398 PMCID: PMC6016741 DOI: 10.1002/hep.28285] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 09/29/2015] [Accepted: 10/09/2015] [Indexed: 01/13/2023]
Abstract
UNLABELLED Monocytes are versatile cells that can fulfill proinflammatory and anti-inflammatory functions when recruited to the liver. Recruited monocytes differentiate into tissue macrophages and dendritic cells, which sample antigens and migrate to lymph nodes to elicit T-cell responses. The signals that determine monocyte differentiation and the role of hepatic sinusoidal endothelial cells (HSECs) in this process are poorly understood. HSECs are known to modulate T-cell activation, which led us to investigate whether transendothelial migration of monocytes across HSECs influences their phenotype and function. Subsets of blood-derived monocytes were allowed to transmigrate across human HSECs into a collagen matrix. Most migrated cells remained in the subendothelial matrix, but ~10% underwent spontaneous basal to apical transendothelial migration. The maturation, cytokine secretion, and T-cell stimulatory capacity of reverse transmigrating (RT) and subendothelial (SE) monocytes were compared. SE monocytes were mainly CD16(-) , whereas 75%-80% of RT monocytes were CD16(+) . SE monocytes derived from the CD14(++) CD16(-) subset and exhibited high phagocytic activity, whereas RT monocytes originated from CD14(++) CD16(+) and CD14(+) CD16(++) monocytes, displayed an immature dendritic cell-like phenotype (CD11c(pos) HLA-DR(pos) CD80lo CD86lo ), and expressed higher levels of chemokine (C-C motif) receptor 8. Consistent with a dendritic cell phenotype, RT monocytes secreted inflammatory cytokines and induced antigen-specific CD4(+) T-cell activation. In contrast, SE monocytes suppressed T-cell proliferation and activation and exhibited endotoxin tolerance. Transcriptome analysis underscored the functional differences between SE and RT monocytes. CONCLUSIONS Migration across HSECs shapes the subsequent fate of monocytes, giving rise to anergic macrophage-like cells in tissue and the release of immunocompetent pre-dendritic cells into the circulation.
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Affiliation(s)
- Henning W Zimmermann
- NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom,Department of Medicine III, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - Tony Bruns
- NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom,Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany,Center for Sepsis Control and Care, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Chris J Weston
- NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Stuart M Curbishley
- NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Evaggelia Liaskou
- NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Ka-Kit Li
- NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Yazid J Resheq
- NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom,Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Paul W. Badenhorst
- School of Immunity and Infection, University of Birmingham, Birmingham, UK
| | - David H Adams
- NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
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33
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Wong YC, Tay SS, McCaughan GW, Bowen DG, Bertolino P. Immune outcomes in the liver: Is CD8 T cell fate determined by the environment? J Hepatol 2015; 63:1005-14. [PMID: 26103545 DOI: 10.1016/j.jhep.2015.05.033] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 05/22/2015] [Accepted: 05/26/2015] [Indexed: 02/07/2023]
Abstract
The liver is known for its tolerogenic properties. This unique characteristic is associated with persistent infection of the liver by the hepatitis B and C viruses. Improper activation of cellular adaptive immune responses within the liver and immune exhaustion over time both contribute to ineffective cytotoxic T cell responses to liver-expressed antigens in animal models, and likely play a role in incomplete clearance of chronic hepatitis virus infections in humans. However, under some conditions, functional immune responses can be elicited against hepatic antigens, resulting in control of hepatotropic infections. In order to develop improved therapeutics in immune-mediated chronic liver diseases, including viral hepatitis, it is essential to understand how intrahepatic immunity is regulated. This review focuses on CD8 T cell immunity directed towards foreign antigens expressed in the liver, and explores how the liver environment dictates the outcome of intrahepatic CD8 T cell responses. Potential strategies to rescue unresponsive CD8 T cells in the liver are also discussed.
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Affiliation(s)
- Yik Chun Wong
- Liver Immunology Group, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia.
| | - Szun Szun Tay
- Liver Immunology Group, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Geoffrey W McCaughan
- Liver Cancer and Injury Group, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - David G Bowen
- Liver Immunology Group, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Patrick Bertolino
- Liver Immunology Group, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia.
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34
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Eckert C, Klein N, Kornek M, Lukacs-Kornek V. The complex myeloid network of the liver with diverse functional capacity at steady state and in inflammation. Front Immunol 2015; 6:179. [PMID: 25941527 PMCID: PMC4403526 DOI: 10.3389/fimmu.2015.00179] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 03/30/2015] [Indexed: 12/23/2022] Open
Abstract
In recent years, it has been an explosion of information regarding the role of various myeloid cells in liver pathology. Macrophages and dendritic cell (DC) play crucial roles in multiple chronic liver diseases such as fibrosis and non-alcoholic fatty liver disease (NAFLD). The complexity of myeloid cell populations and the missing exclusive marker combination make the interpretation of the data often extremely difficult. The current review aims to summarize the multiple roles of macrophages and DCs in chronic liver diseases, especially pointing out how these cells influence liver immune and parenchymal cells thereby altering liver function and pathology. Moreover, the review outlines the currently known marker combinations for the identification of these cell populations for the study of their role in liver immunology.
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Affiliation(s)
- Christoph Eckert
- Department of Medicine II, Saarland University Medical Center , Homburg , Germany
| | - Niklas Klein
- Department of Medicine II, Saarland University Medical Center , Homburg , Germany
| | - Miroslaw Kornek
- Department of Medicine II, Saarland University Medical Center , Homburg , Germany
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35
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Balmasova IP, Yushchuk ND, Mynbaev OA, Alla NR, Malova ES, Shi Z, Gao CL. Immunopathogenesis of chronic hepatitis B. World J Gastroenterol 2014; 20:14156-14171. [PMID: 25339804 PMCID: PMC4202346 DOI: 10.3748/wjg.v20.i39.14156] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Accepted: 04/23/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB) is a widespread infectious disease with unfavorable outcomes and life-threatening consequences for patients, in spite of modern vaccination and antiviral treatment modalities. Cutting-edge experimental approaches have demonstrated key pathways that involve cross-talk between viral particles and host immune cells. All events, including penetration of hepatitis B virus (HBV) particles into host cells, establishing persistence, and chronization of CHB infection, and possibility of complete elimination of HBV particles are controlled by the immune system. Researchers have paid special attention to the replication capacity of HBV in host cells, which is associated with cellular changes that reflect presentation of viral antigens and variability of HBV antigen features. In addition, specific HBV proteins have an immune-modulating ability to initiate molecular mechanisms that “avoid” control by the immune system. The relationship between immunological shifts and chronic infection stages has been intensively studied since it was recognized that the immune system is a direct participant in the recurrent (cyclic) nature of CHB. Understanding the wide diversity of molecular pathways and the crosstalk between innate and adaptive immune system components will provide fresh insight into CHB immune pathogenesis and the possibilities of developing new treatment strategies for this disease.
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36
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Stackaruk ML, Lee AJ, Ashkar AA. Type I interferon regulation of natural killer cell function in primary and secondary infections. Expert Rev Vaccines 2014; 12:875-84. [PMID: 23984959 DOI: 10.1586/14760584.2013.814871] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The priming of natural killer (NK) cells by type I interferon (IFN) is necessary for protection against primary and secondary viral infections. However, the pathway by which type I IFN activates NK cells to elicit antiviral responses is controversial. There is evidence to suggest that type I IFN priming of NK cells occurs through both direct and indirect pathways. As with many innate mechanisms, type I IFN and NK cells also orchestrate the adaptive immune response and thus aid in protection against secondary infections. Type I IFN can shape CD4(+) T cell, B cell and humoral memory formation. In addition, long-lived NK cells can perform specific and enhanced memory-like protection in secondary infections. This review outlines the different mechanisms underlying type I IFN regulation of NK cells and how type I IFN and NK cells can be used as a therapeutic target in vaccinations.
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Affiliation(s)
- Michele L Stackaruk
- Department of Pathology and Molecular Medicine, Institute for Infectious Disease Research, McMaster Immunology Research Centre, McMaster University, Hamilton, MDCL 4015, 1280 Main Street West, Hamilton, L8S 4K1, ON, Canada
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37
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Gordon JR, Ma Y, Churchman L, Gordon SA, Dawicki W. Regulatory dendritic cells for immunotherapy in immunologic diseases. Front Immunol 2014; 5:7. [PMID: 24550907 PMCID: PMC3907717 DOI: 10.3389/fimmu.2014.00007] [Citation(s) in RCA: 132] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Accepted: 01/07/2014] [Indexed: 12/12/2022] Open
Abstract
We recognize well the abilities of dendritic cells to activate effector T cell (Teff cell) responses to an array of antigens and think of these cells in this context as pre-eminent antigen-presenting cells, but dendritic cells are also critical to the induction of immunologic tolerance. Herein, we review our knowledge on the different kinds of tolerogenic or regulatory dendritic cells that are present or can be induced in experimental settings and humans, how they operate, and the diseases in which they are effective, from allergic to autoimmune diseases and transplant tolerance. The primary conclusions that arise from these cumulative studies clearly indicate that the agent(s) used to induce the tolerogenic phenotype and the status of the dendritic cell at the time of induction influence not only the phenotype of the dendritic cell, but also that of the regulatory T cell responses that they in turn mobilize. For example, while many, if not most, types of induced regulatory dendritic cells lead CD4+ naïve or Teff cells to adopt a CD25+Foxp3+ Treg phenotype, exposure of Langerhans cells or dermal dendritic cells to vitamin D leads in one case to the downstream induction of CD25+Foxp3+ regulatory T cell responses, while in the other to Foxp3− type 1 regulatory T cells (Tr1) responses. Similarly, exposure of human immature versus semi-mature dendritic cells to IL-10 leads to distinct regulatory T cell outcomes. Thus, it should be possible to shape our dendritic cell immunotherapy approaches for selective induction of different types of T cell tolerance or to simultaneously induce multiple types of regulatory T cell responses. This may prove to be an important option as we target diseases in different anatomic compartments or with divergent pathologies in the clinic. Finally, we provide an overview of the use and potential use of these cells clinically, highlighting their potential as tools in an array of settings.
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Affiliation(s)
- John R Gordon
- Department of Medicine, University of Saskatchewan , Saskatoon, SK , Canada
| | - Yanna Ma
- Department of Medicine, University of Saskatchewan , Saskatoon, SK , Canada
| | - Laura Churchman
- Department of Medicine, University of Saskatchewan , Saskatoon, SK , Canada
| | - Sara A Gordon
- Department of Medicine, University of Saskatchewan , Saskatoon, SK , Canada
| | - Wojciech Dawicki
- Department of Medicine, University of Saskatchewan , Saskatoon, SK , Canada
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NK cells in hepatitis B virus infection: a potent target for immunotherapy. Arch Virol 2014; 159:1555-65. [PMID: 24445811 DOI: 10.1007/s00705-013-1965-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 12/18/2013] [Indexed: 12/15/2022]
Abstract
Viruses, including hepatitis B virus (HBV), are the most prevalent and infectious agents that lead to liver disease in humans. Hepatocellular carcinoma (HCC) and cirrhosis of the liver are the most serious complications arising from prolonged forms of hepatitis B. Previous studies demonstrated that patients suffering from long-term HBV infections are unable to eradicate HBV from hepatocytes completely. The mechanisms responsible for progression of these forms of infection have not yet been clarified. However, it seems that there are differences in genetic and immunological parameters when comparing patients to subjects who successfully clear HBV infections, and these may represent the causes of long-term infection. Natural killer (NK) cells, the main innate immune cells that target viral infections, play important roles in the eradication of HBV from hepatocytes. NK cells carry several stimulatory and inhibitor receptors, and binding of receptors with their ligands results in activation and suppression of NK cells, respectively. The aim of this review is to address the recent information regarding NK cell phenotype, functions and modifications in hepatitis B. This review addresses the recent data regarding the roles of NK cells as novel targets for immunotherapies that target hepatitis B infection. It also discusses the potential to reduce the risk of HCC or cirrhosis of the liver by targeting NK cells.
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39
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Hudspeth K, Pontarini E, Tentorio P, Cimino M, Donadon M, Torzilli G, Lugli E, Della Bella S, Gershwin ME, Mavilio D. The role of natural killer cells in autoimmune liver disease: a comprehensive review. J Autoimmun 2013; 46:55-65. [PMID: 23880068 DOI: 10.1016/j.jaut.2013.07.003] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2013] [Revised: 06/25/2013] [Accepted: 07/03/2013] [Indexed: 12/29/2022]
Abstract
Natural Killer (NK) cells are important players of the innate arm of the immune system and provide an early defense against pathogens and tumor-transformed cells. Peripheral blood NK (PB-NK) cells were first identified because of their ability to spontaneously kill tumor-cell targets in vitro without the need for specific antigen priming, which is the reason that they were named 'natural killer' cells. The characterization of NK cells in human tissues and body organs represented another important step forward to better understand their physiology and physiopathology. In this regard, many reports revealed over the past decade a differential anatomic distribution of NK cell subsets in several sites such as the intestine, lung, cervix, placenta and liver as well as in secondary lymphoid organs such as spleen, lymph nodes and tonsils. Among all these tissues, the liver is certainly unique as its parenchyma contains an unusually high number of infiltrating immune cells with 30-50% of total lymphocytes being NK cells. Given the constant liver intake of non-self antigens from the gastrointestinal tract via the portal vein, hepatic NK (H-NK) cells must retain a certain degree of tolerance in the context of their immune-surveillance against dangers to the host. Indeed, the breakdown of the tolerogenic state of the liver-associated immune system has been shown to induce autoimmunity. However, the role of NK cells during the course of autoimmune liver diseases is still being debated mainly because a complete characterization of H-NK cells normally resident in healthy human liver has not yet been fully disclosed. Furthermore, the differences in phenotype and functions between human and mouse H-NK cells often preclude translation of results obtained from murine models into experimental approaches to be performed in humans. Here, we provide an extensive characterization of the phenotype of H-NK cells physiologically resident in the human liver by both mentioning data available in literature and including a set of original results recently developed in our laboratory. We then review our current knowledge in regard to the contribution of H-NK cells in regulating local immune homeostasis and tolerance as well as in inducing the development of liver autoimmunity.
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Affiliation(s)
- Kelly Hudspeth
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy
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40
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Li F, Tian Z. The liver works as a school to educate regulatory immune cells. Cell Mol Immunol 2013; 10:292-302. [PMID: 23604044 DOI: 10.1038/cmi.2013.7] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Accepted: 02/21/2013] [Indexed: 12/24/2022] Open
Abstract
Because of its unique blood supply, the liver maintains a special local immune tolerogenic microenvironment. Moreover, the liver can impart this immune tolerogenic effect on other organs, thus inducing systemic immune tolerance. The network of hepatic regulatory cells is an important mechanism underlying liver tolerance. Many types of liver-resident antigen-presenting cells (APCs) have immune regulatory function, and more importantly, they can also induce the differentiation of circulating immune cells into regulatory cells to further extend systemic tolerance. Thus, the liver can be seen as a type of 'school', where liver APCs function as 'teachers' and circulating immune cells function as 'students.'
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Affiliation(s)
- Fenglei Li
- Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China
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41
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Abstract
Organs such as the liver, uterus and lung possess hallmark immunotolerant features, making these organs important for sustaining self-homeostasis. These organs contain a relatively large amount of negative regulatory immune cells, which are believed to take part in the regulation of immune responses. Because natural killer cells constitute a large proportion of all lymphocytes in these organs, increasing attention has been given to the roles that these cells play in maintaining immunotolerance. Here, we review the distribution, differentiation, phenotypic features and functional features of natural killer cells in these immunotolerant organs, in addition to the influence of local microenvironments on these cells and how these factors contribute to organ-specific diseases.
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42
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Li N, Puga Yung GL, Pradier A, Toso C, Giostra E, Morard I, Spahr L, Seebach JD. NK cell isolation from liver biopsies: phenotypic and functional analysis of low cell numbers by flow cytometry. Front Immunol 2013; 4:61. [PMID: 23482713 PMCID: PMC3593626 DOI: 10.3389/fimmu.2013.00061] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Accepted: 02/22/2013] [Indexed: 12/29/2022] Open
Abstract
Natural killer (NK) cells are considered to play a critical role in liver disease. However, the available numbers of intrahepatic lymphocytes (IHL) derived from liver biopsies (LB) for ex vivo analysis of intrahepatic NK cells is very limited; and the isolation method may hamper not only yields and viability, but also phenotype and function of IHL. The aim of the present study was therefore to (1) refine and evaluate the cell yields and viability of a modified isolation protocol from standard size needle LB; and (2) to test the effects of mechanical dissociation and enzymatic tissue digestion, as well as the analysis of very low cell numbers, on the phenotype and function of intrahepatic NK cells. Peripheral blood mononuclear cells (PBMC) and IHL, freshly isolated from the peripheral blood, LB (n = 11) or partial liver resections (n = 5), were used for phenotypic analysis by flow cytometry. NK cell function, i.e., degranulation and cytokine production, was determined by staining of CD107a and intracellular IFN-γ following in vitro stimulation. The mean weight of the LB specimens was 9.1 mg, and a mean number of 7,364 IHL/mg were obtained with a viability of >90%. Exposure of IHL and PBMC to 0.5 mg/ml collagenase IV and 0.02 mg/ml DNase I for 30 min did affect neither the viability, NK cell function, nor the percentages of CD56+, NKp46+, and CD16+ NK cells, whereas the level of CD56 surface expression was reduced. The phenotype of LB-derived NK cells was reliably characterized by acquiring as few as 2,500 IHL per tube for flow cytometry. The functional assay of intrahepatic NK cells was miniaturized by culturing as few as 25,000 IHL in 25 μl (106/ml) using 96-well V-bottom plates with IL-2 and IL-12 overnight, followed by a 4 h stimulation with K562 cells at a NK:K562 ratio of 1:1. In summary, we report reliable phenotypic and functional analyses of small numbers of intrahepatic NK cells isolated from LB specimens providing us with a tool to better address the emerging role of human NK cell immunobiology in liver diseases.
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Affiliation(s)
- Ning Li
- Division of Clinical Immunology and Allergology, Department of Medical Specialties, University Hospital and Medical Faculty Geneva, Switzerland
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43
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Li L, Wozniak LJ, Rodder S, Heish S, Talisetti A, Wang Q, Esquivel C, Cox K, Chen R, McDiarmid SV, Sarwal MM. A common peripheral blood gene set for diagnosis of operational tolerance in pediatric and adult liver transplantation. Am J Transplant 2012; 12:1218-28. [PMID: 22300520 DOI: 10.1111/j.1600-6143.2011.03928.x] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
To identify biomarkers of operational tolerance in pediatric and adult liver transplant recipients, transcriptional profiles were examined from 300 samples by microarrays and Q-PCR measurements of blood specimens from pediatric and adult liver transplant recipients and normal tissues. Tolerance-specific genes were validated in independent samples across two different transplant programs and validated by Q-PCR. A minimal set of 13 unique genes, highly expressed in natural killer cells (p = 0.03), were significantly expressed in both pediatric and adult liver tolerance, irrespective of different clinical and demographic confounders. The performance of this gene set by microarray in independent samples was 100% sensitivity and 83% specificity and the AUC was 0.988 for only three genes by Q-PCR. 26% of adults and 64% of children with excellent liver allograft function, on minimal or dual immunosuppression, showed high prediction scores for tolerance. Novel peripheral transcriptional profiles can be identified in operational tolerance in pediatric and adult recipients of liver allografts, suggesting a high incidence of a pro-tolerogenic phenotype in stable patients on chronic immunosuppression. Given the high incidence of viral infections and malignancies in liver transplant recipients, this gene set provides an important monitoring tool that can move the field toward personalized and predictive medicine in organ transplantation.
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Affiliation(s)
- L Li
- Division of Nephrology, Department of Pediatrics, Stanford University, Palo Alto, CA, USA
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44
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Abstract
Natural killer (NK) cells can be swiftly mobilized by danger signals and are among the earliest arrivals in target organs of disease. However, the role of NK cells in regulating inflammatory responses is far from completely understood in different organs. It is often complex and sometimes paradoxical. The phenotypes and functions of NK cells in the liver, mucosal tissues, uterus, pancreas, joints and brain are influenced by the unique cellular interactions and the local microenvironment within each organ. Hepatic NK cells exhibit an activated phenotype with high levels of cytotoxic effector molecules. These cells have been implicated in promoting liver injury and inhibiting liver fibrosis and regeneration. The liver is also enriched in NK cells with memory-like adaptive immune features. NK cells are detected in healthy lymphoid tissues of the lung, skin and gut, and are recruited to these tissues during infection or inflammation. In the gastrointestinal tract, classical NK cells and a variety of innate lymphoid cells, such as the family of lymphoid tissue-inducer (LTi) cells, are likely to have crucial roles in controlling inflammatory responses. NK cells represent the major lymphocyte subset in the pregnant uterus, with a unique phenotype resembling an early developmental state. Emerging evidence indicates that these cells play a crucial part in mediating the uterine vascular adaptations to pregnancy and promoting the maintenance of healthy pregnancy. In non-obese diabetic (NOD) mice, NK cells are recruited early to the pancreas, become locally activated and then adopt a hyporesponsive phenotype. Although NK cells have a pathogenic role in the natural progression of diabetes in NOD mice, they contribute to diabetes protection induced by complete Freund's adjuvant and to islet allograft tolerance induced by co-stimulatory blockade. NK cells in the inflamed joint uniquely express receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), which promote osteoclast differentiation. Although NK cells have a pathogenic role in collagen-induced arthritis in mice, they are also crucial for protection against antibody-induced arthritis mediated by CpG oligonucleotides. Studies in a mouse model of multiple sclerosis have shown that NK cells arrive in the central nervous system (CNS) before pathogenic T cells and have a protective role in the development of CNS inflammation, probably by killing CNS-resident microglia that prime effector T cells. During evolution, different organs might have evolved distinct ways to recruit and influence the effector functions of NK cells. Once we understand these mechanisms, the next challenge will be to exploit this information for harnessing NK cells to develop prophylactic and therapeutic measures against infectious agents, tumours and inflammatory diseases. Each tissue in our body contains a unique microenvironment that can differentially shape immune reactivity. In this Review article, Shiet al. describe how organ-specific factors influence natural killer cell homing and phenotype, and discuss the local molecular and cellular interactions that determine the protective or pathogenic functions of natural killer cells in the different tissues. Natural killer (NK) cells can be swiftly mobilized by danger signals and are among the earliest arrivals at target organs of disease. However, the role of NK cells in mounting inflammatory responses is often complex and sometimes paradoxical. Here, we examine the divergent phenotypic and functional features of NK cells, as deduced largely from experimental mouse models of pathophysiological responses in the liver, mucosal tissues, uterus, pancreas, joints and brain. Moreover, we discuss how organ-specific factors, the local microenvironment and unique cellular interactions may influence the organ-specific properties of NK cells.
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45
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Abstract
One of the most fundamental problems in immunology is the seemingly schizophrenic ability of the immune system to launch robust immunity against pathogens, while acquiring and maintaining a state of tolerance to the body's own tissues and the trillions of commensal microorganisms and food antigens that confront it every day. A fundamental role for the innate immune system, particularly dendritic cells (DCs), in orchestrating immunological tolerance has been appreciated, but emerging studies have highlighted the nature of the innate receptors and the signaling pathways that program DCs to a tolerogenic state. Furthermore, several studies have emphasized the major role played by cellular interactions and the microenvironment in programming tolerogenic DCs. Here, we review these studies and suggest that the innate control of tolerogenic responses can be viewed as different hierarchies of organization, in which DCs, their innate receptors and signaling networks, and their interactions with other cells and local microenvironments represent different levels of the hierarchy.
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Affiliation(s)
- Santhakumar Manicassamy
- Emory Vaccine Center, Yerkes National Primate Research Center, Department of Pathology, Emory University School of Medicine, Atlanta, GA 30329, USA
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46
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Abstract
Natural killer (NK) cells are bone marrow–derived granular lymphocytes that have a key role in immune defense against viral and bacterial infections and malignancies. NK cells are traditionally defined as cells of the innate immune response because they lack RAG recombinase–dependent clonal antigen receptors. However, evidence suggests that specific subsets of mouse NK cells can nevertheless develop long-lived and highly specific memory to a variety of antigens. Here we review published evidence of NK cell–mediated, RAG-independent adaptive immunity. We also compare and contrast candidate mechanisms for mammalian NK cell memory and antigen recognition with other examples of RAG-independent pathways that generate antigen receptor diversity in non-mammalian species and discuss NK cell memory in the context of lymphocyte evolution.
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Affiliation(s)
- Silke Paust
- Harvard Medical School, Department of Pathology, Boston, Massachusetts, USA
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47
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Krueger PD, Lassen MG, Qiao H, Hahn YS. Regulation of NK cell repertoire and function in the liver. Crit Rev Immunol 2011; 31:43-52. [PMID: 21395510 DOI: 10.1615/critrevimmunol.v31.i1.40] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
NK cells represent a large proportion of the lymphocyte population in the liver and are involved in early innate immunity to pathogen infection. As a result of liver endothelial cell fenestrations, parenchymal cells are not separated by a basal membrane, and thereby pathogen-infected hepatocytes are extensively capable of interacting with innate immune cells including NK cells. In addition, hepatic NK cells interact with surrounding DC and alter their differentiation and function. Recent studies reveal that NK cells exhibit a regulatory function that modulates T cell responses through their interaction with DC and/or direct effect on T cells. Thus, NK cells play a central role, not only in innate immunity, but also in shaping the adaptive immune response. During pathogen infection, there is a remarkable increase of hepatic NK cells, possibly due to the expansion of resident liver NK cells and/or recruitement of NK cells from the blood. The liver microenvironment is believed to modulate hepatic NK cell function through the induction of activating/inhibitory receptor expression and inflammatory cytokine secretion. Particularly, the liver maintains intrahepatic NK cells in a functionally hyporesponsive state compared to splenic NK cells: liver NK cells displayed a dampened IFN-γ response to IL-12/IL-18 stimulation. Notably, the liver contains a significant population of functionally hyporesponsive NK cells that express high levels of the inhibitory receptor NKG2A and lack expression of MHC class I-binding Ly49 receptors. Importantly, adoptively transferred splenic NK cells that migrate to the liver displayed phenotypic and functional changes, supporting a view that the liver environment modifies NK cell receptor expression and functional responsiveness. In this article, we will review studies on the regulation of NK cell repertoire and function in the hepatic environment and the impact of liver NK cell immunoregulatory function on influencing adaptive immunity.
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Affiliation(s)
- Peter D Krueger
- Department of Microbiology, University of Virginia School of Medicine, Charlottesville, 22908, USA
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48
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Nellore A, Fishman JA. NK cells, innate immunity and hepatitis C infection after liver transplantation. Clin Infect Dis 2011; 52:369-77. [PMID: 21217184 DOI: 10.1093/cid/ciq156] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Liver transplantation in patients with active hepatitis C virus (HCV) infection is followed by almost universal recurrence of viral infection. The control of HCV infection has been characterized largely in terms of the HCV-specific function of T-lymphocytes and the adaptive immune response. Emerging data suggest that components of the innate immune system, including natural killer cells, have a central role in determining the nature of posttransplant HCV infection and the likelihood of response to antiviral therapy. This review examines the emerging evidence implicating innate immunity in the pathogenesis of posttransplant HCV infections and the potential therapeutic implications of these observations.
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Affiliation(s)
- Anoma Nellore
- Infectious Disease Division and Transplant Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
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49
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Chan T, Wiltrout RH, Weiss JM. Immunotherapeutic modulation of the suppressive liver and tumor microenvironments. Int Immunopharmacol 2011; 11:879-89. [PMID: 21241810 DOI: 10.1016/j.intimp.2010.12.024] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2010] [Accepted: 12/27/2010] [Indexed: 12/24/2022]
Abstract
The liver is an immunologically unique organ, consisting of resident hematopoietic and parenchymal cells which often contribute to a relatively tolerant microenvironment. It is also becoming increasingly clear that tumor-induced immunosuppression occurs via many of the same cellular mechanisms which contribute to the tolerogenic liver microenvironment. Myeloid cells, consisting of dendritic cells (DC), macrophages and myeloid derived suppressor cells (MDSC), have been implicated in providing a tolerogenic liver environment and immune dysfunction within the tumor microenvironment which can favor tumor progression. As we increase our understanding of the biological mechanisms involved for each phenotypic and/or functionally distinct leukocyte subset, immunotherapeutic strategies can be developed to overcome the inherent barriers to the development of improved strategies for the treatment of liver disease and tumors. In this review, we discuss the principal myeloid cell-based contributions to immunosuppression that are shared between the liver and tumor microenvironments. We further highlight immune-based strategies shown to modulate immunoregulatory cells within each microenvironment and enhance anti-tumor responses.
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Affiliation(s)
- Tim Chan
- NCI Frederick, Building 560, Room 31-18 Frederick, MD 21702, USA
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50
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Abstract
The demands that are imposed on the liver as a result of its function as a metabolic organ that extracts nutrients and clears gut-derived microbial products from the blood are met by a unique microanatomical and immunological environment. The inherent tolerogenicity of the liver and its role in the regulation of innate and adaptive immunity are mediated by parenchymal and non-parenchymal antigen-presenting cells (APCs), cell-autonomous molecular pathways and locally produced factors. Here, we review the central role of liver APCs in the regulation of hepatic immune function and also consider how recent insights may be applied in strategies to target liver tolerance for disease therapy.
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