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Fanijavadi S, Hansen TF, Zedan AH. NK Cell-Microbiota Interaction Biomarker Strategy: Advancing Prostate Cancer Management. Biomolecules 2025; 15:273. [PMID: 40001576 PMCID: PMC11852595 DOI: 10.3390/biom15020273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/06/2025] [Accepted: 02/08/2025] [Indexed: 02/27/2025] Open
Abstract
The role of natural killer (NK) cells in the management of prostate cancer (PCa) remains incompletely understood. Some have proposed that measuring NK cells in blood samples could serve as a reliable, minimally invasive tool for screening, assessing treatment effects, and predicting survival outcomes in PCa patients. However, the significance of different NK cell phenotypes remains unclear. Given the interplay between NK cells and the microbiome, we hypothesize that a combined signature of NK cell phenotypes derived from blood, along with microbiome profiles from oral, urine, and stool samples, could serve as a surrogate marker for NK cell activity in tumor and its microenvironment. Such an approach provides a practical alternative to invasive tumor biopsies by enabling the indirect assessment of NK cell function in tumors. Additionally, profiling NK cell phenotypes and their interactions with the microbiota has the potential to enhance prognostic accuracy and guide the development of personalized therapeutic strategies. Prospective studies are needed to validate the utility of NK cell and microbiome assays in personalized PCa management, with a focus on minimally invasive procedures and predictive signatures for treatment outcomes.
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Affiliation(s)
- Sara Fanijavadi
- Cancer Polyclinic, Levanger Hospital, 7601 Levanger, Norway
- Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, 7100 Vejle, Denmark
| | - Torben Frøstrup Hansen
- Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, 7100 Vejle, Denmark
- Department of Oncology, Institute of Regional Health Research, University of Southern Denmark, 7100 Vejle, Denmark
| | - Ahmed Hussein Zedan
- Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, 7100 Vejle, Denmark
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Razizadeh MH, Zafarani A, Taghavi-Farahabadi M, Khorramdelazad H, Minaeian S, Mahmoudi M. Natural killer cells and their exosomes in viral infections and related therapeutic approaches: where are we? Cell Commun Signal 2023; 21:261. [PMID: 37749597 PMCID: PMC10519079 DOI: 10.1186/s12964-023-01266-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 08/11/2023] [Indexed: 09/27/2023] Open
Abstract
Innate immunity is the first line of the host immune system to fight against infections. Natural killer cells are the innate immunity lymphocytes responsible for fighting against virus-infected and cancerous cells. They have various mechanisms to suppress viral infections. On the other hand, viruses have evolved to utilize different ways to evade NK cell-mediated responses. Viruses can balance the response by regulating the cytokine release pattern and changing the proportion of activating and inhibitory receptors on the surface of NK cells. Exosomes are a subtype of extracellular vesicles that are involved in intercellular communication. Most cell populations can release these nano-sized vesicles, and it was shown that these vesicles produce identical outcomes to the originating cell from which they are released. In recent years, the role of NK cell-derived exosomes in various diseases including viral infections has been highlighted, drawing attention to utilizing the therapeutic potential of these nanoparticles. In this article, the role of NK cells in various viral infections and the mechanisms used by viruses to evade these important immune system cells are initially examined. Subsequently, the role of NK cell exosomes in controlling various viral infections is discussed. Finally, the current position of these cells in the treatment of viral infections and the therapeutic potential of their exosomes are reviewed. Video Abstract.
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Affiliation(s)
- Mohammad Hossein Razizadeh
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Antimicrobial Resistance Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Zafarani
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Taghavi-Farahabadi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Sara Minaeian
- Antimicrobial Resistance Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
| | - Mohammad Mahmoudi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
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De Re V, Tornesello ML, Racanelli V, Prete M, Steffan A. Non-Classical HLA Class 1b and Hepatocellular Carcinoma. Biomedicines 2023; 11:1672. [PMID: 37371767 PMCID: PMC10296335 DOI: 10.3390/biomedicines11061672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/02/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
A number of studies are underway to gain a better understanding of the role of immunity in the pathogenesis of hepatocellular carcinoma and to identify subgroups of individuals who may benefit the most from systemic therapy according to the etiology of their tumor. Human leukocyte antigens play a key role in antigen presentation to T cells. This is fundamental to the host's defense against pathogens and tumor cells. In addition, HLA-specific interactions with innate lymphoid cell receptors, such those present on natural killer cells and innate lymphoid cell type 2, have been shown to be important activators of immune function in the context of several liver diseases. More recent studies have highlighted the key role of members of the non-classical HLA-Ib and the transcript adjacent to the HLA-F locus, FAT10, in hepatocarcinoma. The present review analyzes the major contribution of these molecules to hepatic viral infection and hepatocellular prognosis. Particular attention has been paid to the association of natural killer and Vδ2 T-cell activation, mediated by specific HLA class Ib molecules, with risk assessment and novel treatment strategies to improve immunotherapy in HCC.
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Affiliation(s)
- Valli De Re
- Immunopathology and Cancer Biomarkers Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), 33081 Aviano, Italy;
| | - Maria Lina Tornesello
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy;
| | - Vito Racanelli
- Department of Interdisciplinary Medicine, School of Medicine, ‘Aldo Moro’ University of Bari, 70124 Bari, Italy; (V.R.); (M.P.)
| | - Marcella Prete
- Department of Interdisciplinary Medicine, School of Medicine, ‘Aldo Moro’ University of Bari, 70124 Bari, Italy; (V.R.); (M.P.)
| | - Agostino Steffan
- Immunopathology and Cancer Biomarkers Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), 33081 Aviano, Italy;
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Tembhurne AK, Maheshwari A, Warke H, Chaudhari H, Kerkar SC, Deodhar K, Rekhi B, Mania-Pramanik J. Killer cell immunoglobulin-like receptor (KIR) gene contents: Are they associated with cervical cancer? J Med Virol 2023; 95:e27873. [PMID: 35593263 DOI: 10.1002/jmv.27873] [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: 02/28/2022] [Revised: 04/22/2022] [Accepted: 05/16/2022] [Indexed: 01/11/2023]
Abstract
Killer cell immunoglobulin-like receptors (KIRs) are required for natural killer cell function against virus-infected cells or tumor cells. KIR gene content polymorphisms in Indian women with cervical cancer (CaCx) remain unexplored. Hence, we analyzed the frequencies of KIR genes, KIR haplotypes, and Bx subsets to draw their association with CaCx. The polymerase chain reaction-sequence-specific primer method was used for KIR genotyping in three groups of women: healthy controls (n = 114), women with human papillomavirus (HPV) infection (n = 70), and women with CaCx (n = 120). The results showed that the frequency of KIR2DS5 was significantly higher in women with CaCx compared to women with HPV infection (p = 0.02) and healthy controls (p = 0.01). Whereas the frequency of KIR2DL5B was significantly higher in healthy controls than in women with HPV infection (p = 0.02). The total number of activating KIR genes was higher in women with CaCx than in healthy controls (p = 0.006), indicating their positive association with CaCx. Moreover, the C4T4 subset was higher in women with CaCx than in women with HPV infection, though not significant. In conclusion, our findings highlight KIR2DS5, the C4T4 subset, and activating KIR genes are susceptible factors or positively associated with CaCx. Besides KIR2DL5B, this study also reported for the first time significantly high frequency of KIR2DL1 in healthy controls, indicating its possible protective association against CaCx. Further, significantly high frequency of KIR2DL3 observed in HPV-infected women might be also a promising biomarker for viral infections. Thus, the study confirms the association of KIR genes with cervical cancer in women with HPV infection.
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Affiliation(s)
- Alok K Tembhurne
- ICMR-National Institute for Research in Reproductive Health, Parel, Mumbai, India
| | | | - Himangi Warke
- Seth GS Medical College and King Edward Memorial Hospital, Parel, Mumbai, India
| | - Hemangi Chaudhari
- Seth GS Medical College and King Edward Memorial Hospital, Parel, Mumbai, India
| | - Shilpa C Kerkar
- ICMR-National Institute for Research in Reproductive Health, Parel, Mumbai, India
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Therapeutic Vaccines against Hepatocellular Carcinoma in the Immune Checkpoint Inhibitor Era: Time for Neoantigens? Int J Mol Sci 2022; 23:ijms23042022. [PMID: 35216137 PMCID: PMC8875127 DOI: 10.3390/ijms23042022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/07/2022] [Accepted: 02/10/2022] [Indexed: 02/01/2023] Open
Abstract
Immune checkpoint inhibitors (ICI) have been used as immunotherapy for hepatocellular carcinoma (HCC) with promising but still limited results. Identification of immune elements in the tumor microenvironment of individual HCC patients may help to understand the correlations of responses, as well as to design personalized therapies for non-responder patients. Immune-enhancing strategies, such as vaccination, would complement ICI in those individuals with poorly infiltrated tumors. The prominent role of responses against mutated tumor antigens (neoAgs) in ICI-based therapies suggests that boosting responses against these epitopes may specifically target tumor cells. In this review we summarize clinical vaccination trials carried out in HCC, the available information on potentially immunogenic neoAgs in HCC patients, and the most recent results of neoAg-based vaccines in other tumors. Despite the low/intermediate mutational burden observed in HCC, data obtained from neoAg-based vaccines in other tumors indicate that vaccines directed against these tumor-specific antigens would complement ICI in a subset of HCC patients.
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Harrison GF, Leaton LA, Harrison EA, Kichula KM, Viken MK, Shortt J, Gignoux CR, Lie BA, Vukcevic D, Leslie S, Norman PJ. Allele imputation for the killer cell immunoglobulin-like receptor KIR3DL1/S1. PLoS Comput Biol 2022; 18:e1009059. [PMID: 35192601 PMCID: PMC8896733 DOI: 10.1371/journal.pcbi.1009059] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 03/04/2022] [Accepted: 01/10/2022] [Indexed: 12/15/2022] Open
Abstract
Highly polymorphic interaction of KIR3DL1 and KIR3DS1 with HLA class I ligands modulates the effector functions of natural killer (NK) cells and some T cells. This genetically determined diversity affects severity of infections, immune-mediated diseases, and some cancers, and impacts the course of immunotherapies, including transplantation. KIR3DL1 is an inhibitory receptor, and KIR3DS1 is an activating receptor encoded by the KIR3DL1/S1 gene that has more than 200 diverse and divergent alleles. Determination of KIR3DL1/S1 genotypes for medical application is hampered by complex sequence and structural variation, requiring targeted approaches to generate and analyze high-resolution allele data. To overcome these obstacles, we developed and optimized a model for imputing KIR3DL1/S1 alleles at high-resolution from whole-genome SNP data. We designed the model to represent a substantial component of human genetic diversity. Our Global imputation model is effective at genotyping KIR3DL1/S1 alleles with an accuracy ranging from 88% in Africans to 97% in East Asians, with mean specificity of 99% and sensitivity of 95% for alleles >1% frequency. We used the established algorithm of the HIBAG program, in a modification named Pulling Out Natural killer cell Genomics (PONG). Because HIBAG was designed to impute HLA alleles also from whole-genome SNP data, PONG allows combinatorial diversity of KIR3DL1/S1 with HLA-A and -B to be analyzed using complementary techniques on a single data source. The use of PONG thus negates the need for targeted sequencing data in very large-scale association studies where such methods might not be tractable.
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Affiliation(s)
- Genelle F. Harrison
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America
- Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Laura Ann Leaton
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America
- Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Erica A. Harrison
- Independent Researcher, Broomfield, Colorado, United States of America
| | - Katherine M. Kichula
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America
- Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Marte K. Viken
- Department of Immunology, University of Oslo and Oslo University Hospital, Oslo, Norway
- Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Jonathan Shortt
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Christopher R. Gignoux
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Benedicte A. Lie
- Department of Immunology, University of Oslo and Oslo University Hospital, Oslo, Norway
- Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Damjan Vukcevic
- School of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia
- Melbourne Integrative Genomics, University of Melbourne, Parkville, Victoria, Australia
| | - Stephen Leslie
- School of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia
- Melbourne Integrative Genomics, University of Melbourne, Parkville, Victoria, Australia
- School of BioSciences, University of Melbourne, Parkville, Victoria, Australia
| | - Paul J. Norman
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America
- Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States of America
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Umemura T, Joshita S, Saito H, Wakabayashi SI, Kobayashi H, Yamashita Y, Sugiura A, Yamazaki T, Ota M. Investigation of the Effect of KIR-HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients. Cancers (Basel) 2021; 13:cancers13133267. [PMID: 34209910 PMCID: PMC8267716 DOI: 10.3390/cancers13133267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/21/2021] [Accepted: 06/25/2021] [Indexed: 11/21/2022] Open
Abstract
Simple Summary Natural killer (NK) cells normally respond to tumor cells and virally infected cells by killing them via the innate immune system. However, the functional impairment of NK cells has been observed in hepatocellular carcinoma. The NK-cell phenotype is partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This study evaluated the involvement of KIR–HLA pairs in hepatocellular carcinoma development in 211 patients with hepatitis C virus-associated cirrhosis. HLA-Bw4 and the KIR3DL1+HLA-Bw4 pair were significantly associated with hepatocellular carcinoma onset during a median follow-up of 6.6 years, which suggested that functional interactions between KIR and HLA or HLA-Bw4 may influence the risk of cancer development. Abstract Natural killer cells are partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This investigation examined the risk of hepatocellular carcinoma (HCC) in relation to KIR–HLA pairs in patients with compensated hepatitis C virus (HCV)-associated cirrhosis. A total of 211 Japanese compensated HCV cirrhotic cases were retrospectively enrolled. After KIR, HLA-A, HLA-Bw, and HLA-C typing, associations between HLA, KIR, and KIR–HLA combinations and HCC development were evaluated using the Cox proportional hazards model with the stepwise method. During a median follow-up period of 6.6 years, 69.7% of patients exhibited HCC. The proportions of HLA-Bw4 and the KIR3DL1 + HLA-Bw4 pair were significantly higher in patients with HCC than in those without (78.9% vs. 64.1%; odds ratio (OR)—2.10, 95% confidence interval (CI)—1.10–4.01; p = 0.023 and 76.2% vs. 60.9%, odds ratio—2.05, p = 0.024, respectively). Multivariate analysis revealed the factors of male gender (hazard ratio (HR)—1.56, 95% CI—1.12–2.17; p = 0.009), α-fetoprotein > 5.6 ng/mL (HR—1.56, 95% CI—1.10–2.10; p = 0.011), and KIR3DL1 + HLA-Bw4 (HR—1.69, 95% CI—1.15–2.48; p = 0.007) as independent risk factors for developing HCC. Furthermore, the cumulative incidence of HCC was significantly higher in patients with KIR3DL1 + HLA-Bw4 than in those without (log-rank test; p = 0.013). The above findings suggest KIR3DL1 + HLA-Bw4, in addition to HLA-Bw4, as a novel KIR–HLA pair possibly associated with HCC development in HCV cirrhosis. HCV-associated cirrhotic patients with the risk factors of male gender, α-fetoprotein > 5.6 ng/mL, and KIR3DL1 + HLA-Bw4 may require careful surveillance for HCC onset.
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Affiliation(s)
- Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
- Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto 390-8621, Nagano, Japan
- Department of Life Innovation, Shinshu University, Matsumoto 390-8621, Nagano, Japan
- Correspondence: ; Tel.: +81-263-37-2634; Fax: +81-263-32-9412
| | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
| | - Hiromi Saito
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
| | - Shun-ichi Wakabayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
| | - Hiroyuki Kobayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
| | - Yuki Yamashita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
| | - Ayumi Sugiura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
| | - Tomoo Yamazaki
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
| | - Masao Ota
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
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Bozward AG, Warricker F, Oo YH, Khakoo SI. Natural Killer Cells and Regulatory T Cells Cross Talk in Hepatocellular Carcinoma: Exploring Therapeutic Options for the Next Decade. Front Immunol 2021; 12:643310. [PMID: 33995362 PMCID: PMC8120158 DOI: 10.3389/fimmu.2021.643310] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 04/12/2021] [Indexed: 12/12/2022] Open
Abstract
Despite major advances in immunotherapy, hepatocellular carcinoma (HCC) remains a challenging target. Natural Killer (NK) cells are crucial components of the anti-HCC immune response, which can be manipulated for immunotherapeutic benefit as primary targets, modulators of the tumour microenvironment and in synchronising with tumour antigen specific effector CD8 cells for tumour clearance. Regulatory T cells shape the anti-tumour response from effector T cells via multiple suppressive mechanisms. Future research is needed to address the development of novel NK cell-targeted immunotherapy and on restraining Treg frequency and function in HCC. We have now entered a new era of anti-cancer treatment using checkpoint inhibitor (CPI)-based strategies. Combining GMP-NK cell immunotherapy to enhance the frequency of NK cells with CPI targeting both NK and CD8 T cells to release co-inhibitory receptors and enhance the cells anti-tumour immunity of HCC would be an attractive therapeutic option in the treatment of HCC. These therapeutic approaches should now be complemented by the application of genomic, proteomic and metabolomic approaches to understanding the microenvironment of HCC which, together with deep immune profiling of peripheral blood and HCC tissue before and during treatment, will provide the much-needed personalised medicine approach required to improve clinical outcomes for patients with HCC.
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Affiliation(s)
- Amber G. Bozward
- Centre for Liver and Gastroenterology Research and National Institute for Health Research Biomedical Research Centre (NIHR BRC) Birmingham, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre- Rare Liver, Birmingham, United Kingdom
| | - Frazer Warricker
- The School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
- NIHR Biomedical Research Centre, The School of Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom
| | - Ye H. Oo
- Centre for Liver and Gastroenterology Research and National Institute for Health Research Biomedical Research Centre (NIHR BRC) Birmingham, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre- Rare Liver, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Salim I. Khakoo
- The School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
- NIHR Biomedical Research Centre, The School of Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom
- Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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9
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Human NK Cells in Autologous Hematopoietic Stem Cell Transplantation for Cancer Treatment. Cancers (Basel) 2021; 13:cancers13071589. [PMID: 33808201 PMCID: PMC8037172 DOI: 10.3390/cancers13071589] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/25/2021] [Accepted: 03/26/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Natural killer (NK) cells are key elements of the innate immune system that have the ability to kill transformed (tumor and virus-infected) cells without prior sensitization. Hematopoietic stem cell transplantation (HSCT) is a medical procedure used in the treatment of a variety of cancers. The early reconstitution of NK cells after HSCT and their functions support the therapeutic potential of these cells in allogenic HSCT. However, the role of NK cells in autologous HSCT is less clear. In this review, we have summarized general aspects of NK cell biology. In addition, we have also reviewed factors that affect autologous HSCT outcome, with particular attention to the role played by NK cells. Abstract Natural killer (NK) cells are phenotypically and functionally diverse lymphocytes with the ability to recognize and kill malignant cells without prior sensitization, and therefore, they have a relevant role in tumor immunosurveillance. NK cells constitute the main lymphocyte subset in peripheral blood in the first week after hematopoietic stem cell transplantation (HSCT). Although the role that NK cells play in allogenic HSCT settings has been documented for years, their significance and beneficial effects associated with the outcome after autologous HSCT are less recognized. In this review, we have summarized fundamental aspects of NK cell biology, such as, NK cell subset diversity, their effector functions, and differentiation. Moreover, we have reviewed the factors that affect autologous HSCT outcome, with particular attention to the role played by NK cells and their receptor repertoire in this regard.
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Ursu LD, Calenic B, Diculescu M, Dima A, Stoian IT, Constantinescu I. Clinical and histopathological changes in different KIR gene profiles in chronic HCV Romanian patients. Int J Immunogenet 2020; 48:16-24. [PMID: 32961633 DOI: 10.1111/iji.12515] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/27/2020] [Accepted: 09/02/2020] [Indexed: 11/30/2022]
Abstract
Hepatitis C virus (HCV)-infected individuals may have a faster progression of liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC) development when influenced by host, viral and environmental factors. Hepatitis C virus disease progression is also associated with genetic variants of specific killer cell immunoglobulin-like receptors (KIRs) and genes of the major histocompatibility complex (MHC). The aim of the present study was to correlate clinical, virologic and biochemical parameters and to evaluate the possible influence of KIR genes and their HLA class I ligands in patients infected with hepatitis C virus. The present study analysed a total of 127 chronic HCV-infected patients for various biochemical and genetics factors that can influence disease progression and prognosis. Liver function parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), direct bilirubin (DB), alpha-fetoprotein (AFP), HCV RNA levels and fibrosis indices were analysed using well-established biochemical methods. At the same time, KIR and HLA genotyping was performed using a polymerase chain reaction sequence-specific primer technique. Analysis of HLA class I and HLA ligands revealed that HLA-C*12:02 and HLA-A3 and HLA-A11 were positively associated with the F3-F4 fibrosis group (p = .026; OR = 8.717, CI = 1.040-73.077; respectively, p = .047; OR = 2.187; 95% CI = 1.066-4.486). KIR2DL2-positive patients had high median levels of AST after treatment and direct bilirubin levels when compared to KIR2DL2-negative patients (p = .013, respectively, p = .028). KIR2DL2/KIR2DL2-C1C1 genotype was associated with increased AST, ALT and GGT levels. A higher GGT level was also observed in KIR2DS2-C1-positive patients when compared to KIR2DS2-C1-negative patients. The present research demonstrates several links between specific clinical, virologic and biochemical parameters and the expression of KIR genes and their HLA ligands in HCV-infected patients. These connections should be taken into account when considering disease development and treatment.
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Affiliation(s)
- Larisa Denisa Ursu
- Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Bogdan Calenic
- Department of Biochemistry, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Mircea Diculescu
- Gastroenterology and Hepatology Department, Fundeni Clinical Institute, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Alina Dima
- Rheumatology Department, Colentina Clinical Hospital, Bucharest, Romania
| | - Iulia Teodora Stoian
- Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Ileana Constantinescu
- Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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11
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Vidal-Castiñeira JR, López-Vázquez A, Diaz-Bulnes P, Díaz-Coto S, Márquez-Kisinousky L, Martínez-Borra J, Navascues CA, Sanz-Cameno P, de la Vega J, Astudillo A, Rodríguez M, López-Larrea C. Genetic contribution of endoplasmic reticulum aminopeptidase 1 polymorphisms to liver fibrosis progression in patients with HCV infection. J Mol Med (Berl) 2020; 98:1245-1254. [PMID: 32647953 DOI: 10.1007/s00109-020-01948-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 06/24/2020] [Accepted: 06/30/2020] [Indexed: 12/21/2022]
Abstract
The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses, trimming peptides and loading onto HLA class I molecules. Coding single nucleotide polymorphisms within ERAP1 are associated with autoimmune diseases, viral infections, and cancer development. Our purpose was to analyze the influence of ERAP1 variants on fibrogenesis in hepatitis C virus (HCV)-infected patients. A range of ERAP1 polymorphisms were genotyped in 722 unrelated Caucasian patients diagnosed with chronic HCV from two Spanish cohorts. Patients were classified according to their fibrosis stage. Paraffin-embedded tissue microarrays were constructed to assess ERAP1 expression (HCV = 38; alcoholic = 20) by immunohistochemistry. A statistical algorithm was applied to derive a fibrogenesis prediction model. The ERAP1 variants rs30187/T (K528, pc < 0.001) and rs27044/G (Q730, pc < 0.001) were related with severe fibrosis. These results were validated in the two independent cohorts. Furthermore, patients with the rs30187/T allele had stronger ERAP1 protein expression than those with the rs30187/C (p < 0.05). The statistical model showed that patients with rs30187 C/T and T/T genotypes took 15.58 years (median) to develop advanced fibrosis, but this value was 32.08 years in patients carrying C/C genotype (p < 0.005). ERAP1 variants may influence the clinical course of fibrogenesis in HCV-infected patients. These polymorphisms could be exploited as constitutive new markers of fibrosis evolution. The results highlight the possibility of using modulators of ERAP1 to generate a protective immune response against chronic HCV infection. KEY MESSAGES: What is known Several ERAP1 polymorphisms are associated with autoimmune diseases and cancer. ERAP1 trims peptides to HLA class I presentation. What is new here ERAP1 polymorphisms are associated with fibrogenesis. The ERAP1 polymorphisms genotype could help us in clinical management of patients. Potential translational impact The use of modulators of ERAP1 could generate a protective response depending on SNPs.
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Affiliation(s)
- Jose Ramón Vidal-Castiñeira
- Translational Immunology Laboratory, Health Research Institute of the Principality of Asturias (ISPA), Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Antonio López-Vázquez
- Translational Immunology Laboratory, Health Research Institute of the Principality of Asturias (ISPA), Hospital Universitario Central de Asturias, Oviedo, Spain.,Immunology Service, Hospital Universitario Central de Asturias, Av. de Roma s/n, 33011, Oviedo, Spain
| | - Paula Diaz-Bulnes
- Translational Immunology Laboratory, Health Research Institute of the Principality of Asturias (ISPA), Hospital Universitario Central de Asturias, Oviedo, Spain
| | | | - Leonardo Márquez-Kisinousky
- Translational Immunology Laboratory, Health Research Institute of the Principality of Asturias (ISPA), Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Jesús Martínez-Borra
- Translational Immunology Laboratory, Health Research Institute of the Principality of Asturias (ISPA), Hospital Universitario Central de Asturias, Oviedo, Spain.,Immunology Service, Hospital Universitario Central de Asturias, Av. de Roma s/n, 33011, Oviedo, Spain
| | - Carmen A Navascues
- Gastroenterology Service, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Paloma Sanz-Cameno
- Liver Unit, Gastroenterology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid and CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Juan de la Vega
- Gastroenterology Service, Hospital San Agustín, Avilés, Spain
| | - Aurora Astudillo
- Pathology Service, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Manuel Rodríguez
- Gastroenterology Service, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Carlos López-Larrea
- Translational Immunology Laboratory, Health Research Institute of the Principality of Asturias (ISPA), Hospital Universitario Central de Asturias, Oviedo, Spain. .,Immunology Service, Hospital Universitario Central de Asturias, Av. de Roma s/n, 33011, Oviedo, Spain.
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12
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Chaisri S, Jumnainsong A, Romphruk A, Leelayuwat C. The effect of KIR and HLA polymorphisms on dengue infection and disease severity in northeastern Thais. Med Microbiol Immunol 2020; 209:613-620. [PMID: 32524212 DOI: 10.1007/s00430-020-00685-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 06/02/2020] [Indexed: 10/24/2022]
Abstract
Killer cell immunoglobulin-like receptors (KIRs) are cell surface receptors on natural killer (NK) cells and subsets of T cells. The interaction between KIRs and their cognate ligands (Human leukocyte antigen class I molecules, HLA class I) modulates the immune response of NK cells, in particular through clearance of virus-infected cells. Here, we investigated the effect of KIRs and HLA ligands on dengue infections and disease severity. The KIRs and HLA ligands were identified in 235 healthy controls (HC) and 253 dengue patients (DEN) using polymerase chain reaction with sequence specific primer (PCR-SSP); moreover, DEN was classified to 100 dengue fever (DF) and 153 dengue haemorrhagic fever (DHF). Risks were expressed as odds ratios (ORs) and 95% confidence intervals (CIs) with significance set at a two-tailed P value of < 0.05. The Bonferroni correction was applied for multiple comparisons. Twelve significant associations were observed in dengue infections and disease severity; however, two outcomes survived after the Bonferroni correction. Of these, HLA-A11 was associated with an increased risk to develop dengue disease (OR 2.41, 95% CI 1.62-3.60, Pc = 0.004), while KIR3DS1+ Bw4 was a protective genotype to developing DHF (OR 0.28, 95% CI 0.16-0.48, Pc < 0.001). This study revealed an important role of KIR and HLA ligands in innate immune responses to dengue viral infections and, in particular, their effect on clinical outcomes and disease severity.
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Affiliation(s)
- Suwit Chaisri
- Chulabhorn International College of Medicine (CICM), Thammasat University, Pathum Thani, 12121, Thailand.,The Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Amonrat Jumnainsong
- The Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand.,Department of Clinical Immunology and Transfusion Sciences, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Amornrat Romphruk
- The Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand.,Blood Transfusion Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Chanvit Leelayuwat
- The Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand. .,Department of Clinical Immunology and Transfusion Sciences, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand.
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13
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Auer ED, Tong HV, Amorim LM, Malheiros D, Hoan NX, Issler HC, Petzl-Erler ML, Beltrame MH, Boldt ABW, Toan NL, Song LH, Velavan TP, Augusto DG. Natural killer cell receptor variants and chronic hepatitis B virus infection in the Vietnamese population. Int J Infect Dis 2020; 96:541-547. [PMID: 32422377 DOI: 10.1016/j.ijid.2020.05.033] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/05/2020] [Accepted: 05/07/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES Genes of host immunity play an important role in disease pathogenesis and are determinants of clinical courses of infections, including hepatitis B virus (HBV). Killer-cell immunoglobulin-like receptor (KIR), expressed on the surface of natural killer cells (NK), regulate NK cell cytotoxicity by interacting with human leukocyte antigen (HLA) class I molecules and are candidates for influencing the course of HBV. This study evaluated whether variations in KIR gene content and HLA-C ligands are associated with HBV and with the development of liver cirrhosis and hepatocellular carcinoma. METHODS A Vietnamese study cohort (HBV n = 511; controls n = 140) was genotyped using multiplex sequence-specific polymerase chain reaction (PCR-SSP) followed by melting curve analysis. RESULTS The presence of the functional allelic group of KIR2DS4 was associated with an increased risk of chronic HBV (OR = 1.86, pcorr = 0.02), while KIR2DL2+HLA-C1 (OR = 0.62, pcorr = 0.04) and KIR2DL3+HLA-C1 (OR = 0.48, pcorr = 0.04) were associated with a decreased risk. The pair KIR2DL3+HLA-C1 was associated with liver cirrhosis (OR = 0.40, pcorr = 0.01). The presence of five or more activating KIR variants was associated with hepatocellular carcinoma (OR = 0.53, pcorr = 0.04). CONCLUSIONS KIR gene content variation and combinations KIR-HLA influence the outcome of HBV infection.
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Affiliation(s)
- Eduardo Delabio Auer
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná (UFPR), Curitiba, Brazil
| | - Hoang Van Tong
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Viet Nam; Vietnamese German Center for Medical Research (VGCARE), Hanoi, Viet Nam
| | - Leonardo Maldaner Amorim
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná (UFPR), Curitiba, Brazil
| | - Danielle Malheiros
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná (UFPR), Curitiba, Brazil
| | - Nghiem Xuan Hoan
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Vietnamese German Center for Medical Research (VGCARE), Hanoi, Viet Nam; Institute of Clinical Infectious Diseases, Hanoi, Viet Nam
| | - Hellen Caroline Issler
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná (UFPR), Curitiba, Brazil
| | - Maria Luiza Petzl-Erler
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná (UFPR), Curitiba, Brazil
| | - Márcia Holsbach Beltrame
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná (UFPR), Curitiba, Brazil
| | - Angelica Beate Winter Boldt
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná (UFPR), Curitiba, Brazil
| | - Nguyen Linh Toan
- Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Viet Nam; Vietnamese German Center for Medical Research (VGCARE), Hanoi, Viet Nam
| | - Le Huu Song
- Vietnamese German Center for Medical Research (VGCARE), Hanoi, Viet Nam; Institute of Clinical Infectious Diseases, Hanoi, Viet Nam
| | - Thirumalaisamy P Velavan
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Vietnamese German Center for Medical Research (VGCARE), Hanoi, Viet Nam; Faculty of Medicine, Duy Tan University, Da Nang, Viet Nam.
| | - Danillo G Augusto
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná (UFPR), Curitiba, Brazil.
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14
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Njiomegnie GF, Read SA, Fewings N, George J, McKay F, Ahlenstiel G. Immunomodulation of the Natural Killer Cell Phenotype and Response during HCV Infection. J Clin Med 2020; 9:jcm9041030. [PMID: 32268490 PMCID: PMC7230811 DOI: 10.3390/jcm9041030] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 03/30/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatitis C virus (HCV) infection develops into chronic hepatitis in over two-thirds of acute infections. While current treatments with direct-acting antivirals (DAAs) achieve HCV eradication in >95% of cases, no vaccine is available and re-infection can readily occur. Natural killer (NK) cells represent a key cellular component of the innate immune system, participating in early defence against infectious diseases, viruses, and cancers. When acute infection becomes chronic, however, NK cell function is altered. This has been well studied in the context of HCV, where changes in frequency and distribution of NK cell populations have been reported. While activating receptors are downregulated on NK cells in both acute and chronic infection, NK cell inhibiting receptors are upregulated in chronic HCV infection, leading to altered NK cell responsiveness. Furthermore, chronic activation of NK cells following HCV infection contributes to liver inflammation and disease progression through enhanced cytotoxicity. Consequently, the NK immune response is a double-edged sword that is a significant component of the innate immune antiviral response, but persistent activation can drive tissue damage during chronic infection. This review will summarise the role of NK cells in HCV infection, and the changes that occur during HCV therapy.
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Affiliation(s)
- Gaitan Fabrice Njiomegnie
- Blacktown Clinical School and Research Centre, Western Sydney University, Blacktown 2148, NSW, Australia (S.A.R.)
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia
| | - Scott A. Read
- Blacktown Clinical School and Research Centre, Western Sydney University, Blacktown 2148, NSW, Australia (S.A.R.)
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia
- Blacktown Hospital, Blacktown 2148, NSW, Australia
| | - Nicole Fewings
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Westmead 2145, NSW, Australia
- Westmead Clinical School, University of Sydney, Westmead 2145, NSW, Australia
| | - Jacob George
- Blacktown Clinical School and Research Centre, Western Sydney University, Blacktown 2148, NSW, Australia (S.A.R.)
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia
- Westmead Clinical School, University of Sydney, Westmead 2145, NSW, Australia
- Westmead Hospital, Westmead 2145, NSW, Australia
| | - Fiona McKay
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Westmead 2145, NSW, Australia
- Westmead Clinical School, University of Sydney, Westmead 2145, NSW, Australia
| | - Golo Ahlenstiel
- Blacktown Clinical School and Research Centre, Western Sydney University, Blacktown 2148, NSW, Australia (S.A.R.)
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia
- Blacktown Hospital, Blacktown 2148, NSW, Australia
- Westmead Clinical School, University of Sydney, Westmead 2145, NSW, Australia
- Correspondence: ; Tel.: +61-2-9851-6073
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15
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Blunt MD, Khakoo SI. Activating killer cell immunoglobulin-like receptors: Detection, function and therapeutic use. Int J Immunogenet 2020; 47:1-12. [PMID: 31755661 DOI: 10.1111/iji.12461] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 10/24/2019] [Indexed: 12/15/2022]
Abstract
Killer cell immunoglobulin-like receptors (KIRs) have a central role in the control of natural killer (NK) cell function. The functions of the activating KIRs, as compared to those of the inhibitory KIR, have been more difficult to define due to difficulties in antibody-mediated identification and their apparent low affinities for HLA class I. Immunogenetic studies have shown associations of activating KIRs with the outcome of autoimmune diseases, pregnancy-associated disorders, infectious diseases and cancers. Activating KIR are thus thought to have important roles in the control of natural killer cell functions and their role in disease. In this review, we discuss current knowledge on activating KIR, their ligands and, their roles in the pathogenesis and potential therapy of human diseases.
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Affiliation(s)
- Matthew D Blunt
- Clinical and Experimental Sciences, Faculty of Medicine, Southampton General Hospital, University of Southampton, Southampton, UK
| | - Salim I Khakoo
- Clinical and Experimental Sciences, Faculty of Medicine, Southampton General Hospital, University of Southampton, Southampton, UK
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16
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The Evolutionary Arms Race between Virus and NK Cells: Diversity Enables Population-Level Virus Control. Viruses 2019; 11:v11100959. [PMID: 31627371 PMCID: PMC6832630 DOI: 10.3390/v11100959] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 10/11/2019] [Accepted: 10/14/2019] [Indexed: 12/13/2022] Open
Abstract
Viruses and natural killer (NK) cells have a long co-evolutionary history, evidenced by patterns of specific NK gene frequencies in those susceptible or resistant to infections. The killer immunoglobulin-like receptors (KIR) and their human leukocyte antigen (HLA) ligands together form the most polymorphic receptor-ligand partnership in the human genome and govern the process of NK cell education. The KIR and HLA genes segregate independently, thus creating an array of reactive potentials within and between the NK cell repertoires of individuals. In this review, we discuss the interplay between NK cell education and adaptation with virus infection, with a special focus on three viruses for which the NK cell response is often studied: human immunodeficiency virus (HIV), hepatitis C virus (HCV) and human cytomegalovirus (HCMV). Through this lens, we highlight the complex co-evolution of viruses and NK cells, and their impact on viral control.
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17
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Cariani E, Missale G. Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications. Liver Int 2019; 39:1608-1621. [PMID: 31314948 DOI: 10.1111/liv.14192] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/02/2019] [Accepted: 07/03/2019] [Indexed: 02/06/2023]
Abstract
The development of immunotherapy for solid tumours has boosted interest in the contexture of tumour immune microenvironment (TIME). Several lines of evidence indicate that the interplay between tumour cells and TIME components is a key factor for the evolution of hepatocellular carcinoma (HCC) and for the likelihood of response to immunotherapeutics. The availability of high-resolution methods will be instrumental for a better definition of the complexity and diversity of TIME with the aim of predicting disease outcome, treatment response and possibly new therapeutic targets. Here, we review current knowledge about the immunological mechanisms involved in shaping the clinical course of HCC. Effector cells, regulatory cells and soluble mediators are discussed for their role defining TIME and as targets for immune modulation, together with possible immune signatures for optimization of immunotherapeutic strategies.
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Affiliation(s)
- Elisabetta Cariani
- Toxicology and Advanced Diagnostics, Ospedale S. Agostino-Estense, Modena, Italy
| | - Gabriele Missale
- Department of Medicine and Surgery, University of Parma, Parma, Italy
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18
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HLA-F on Autologous HIV-Infected Cells Activates Primary NK Cells Expressing the Activating Killer Immunoglobulin-Like Receptor KIR3DS1. J Virol 2019; 93:JVI.00933-19. [PMID: 31270222 DOI: 10.1128/jvi.00933-19] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 06/25/2019] [Indexed: 01/23/2023] Open
Abstract
HIV-exposed seronegative KIR3DS1 homozygotes have a reduced risk of HIV infection. HLA-F is the ligand for the activating NK cell receptor (NKR) KIR3DS1. HLA-F is expressed on HIV-infected CD4 T cells. Coculture of sorted, HIV-infected CD4- (siCD4-) T cells with NK cells activated a higher frequency of KIR3DS1+ than KIR3DS1- NK cells from KIR3DS1 homozygotes to elicit anti-HIV functions such as CCL4, gamma interferon (IFN-γ), and CD107a expression. This was the case whether KIR3DS1+/- NK cells were analyzed inclusively or exclusively by gating out NK cells coexpressing the NKRs, KIR2DL1/L2/L3, 3DL2, KIR2DS1/S2/S3/S5, NKG2A, and ILT2. Blocking the interaction of HLA-F on siCD4- cells with KIR3DS1 on exclusively gated KIR3DS1+ NK cells with KIR3DS1-Fc chimeric protein or an HLA-F-specific monoclonal antibody reduced the frequency of activated KIR3DS1+ cells compared to that under control conditions. KIR3DS1+ NK cell activation by HIV-infected CD4+ cells may underlie the reduced risk of KIR3DS1 homozygotes to HIV infection.IMPORTANCE This study investigated a mechanism that may underly epidemiological studies showing that carriage of the KIR3DS1 homozygous genotype is more frequent among HIV-exposed seronegative subjects than among HIV-susceptible individuals. Carriage of this genotype is associated with a reduced risk of HIV infection. The protective mechanism involves the interaction of HLA-F on CD4+ cells infected with replication-competent HIV with the activating NK receptor, KIR3DS1. This interaction leads to the activation of KIR3DS1+ NK cells for secretion of cytokines and chemokines with anti-HIV activity. Among these is CCL4, which binds and blocks CCR5, the coreceptor for HIV entry of HIV into new target cells. In the setting of an exposure to HIV, incoming HIV-infected cells expressing HLA-F rapidly activate KIR3DS1+ NK cells to elicit anti-HIV activity. Exclusive gating strategies and blocking experiments support the notion that the HLA-F/KIR3DS1 interaction is sufficient to activate NK cell functions.
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19
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Abstract
Natural killer (NK) cells are bone marrow-derived large granular lymphocytes defined by CD3negCD56pos and represent 5% to 25% of peripheral blood mononuclear cell fraction of the healthy humans. NK cells have a highly specific and sophisticated target cell recognition receptor system arbitrated by the integration of signals triggered by a multitude of inhibitory and activating receptors. Human NK cells express distinct families of receptors, including (1) killer cell immunoglobulin-like receptors, (2) killer cell lectin-like receptors, (3) leukocyte immunoglobulin-like receptors, and (4) natural cytotoxicity receptors.
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Affiliation(s)
- Raja Rajalingam
- Department of Surgery, Immunogenetics and Transplantation Laboratory, University of California San Francisco, 3333 California Street, Suite 150, San Francisco, CA 94118, USA.
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20
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Li Q, Liu S, Zhang S, Liu C, Sun M, Li C, Zhang X, Chen J, Yao Y, Shi L. Human leucocyte antigen but not KIR alleles and haplotypes associated with chronic HCV infection in a Chinese Han population. Int J Immunogenet 2019; 46:263-273. [PMID: 30932338 DOI: 10.1111/iji.12425] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 02/28/2019] [Accepted: 03/07/2019] [Indexed: 12/12/2022]
Abstract
The host immune system plays a key role in the elimination of infected cells which depend on killer-cell immunoglobulin-like receptors (KIR), human leucocyte antigen (HLA) class I molecules and their combinations. To evaluate the roles of HLAclass I, KIR genes and their combination in Chronic hepatitis C virus (HCV) infection (CHC), a total of 301 CHCs and 239 controls in a Chinese Han population were included for HLA and KIR genotyping using next-generation sequencing and multiplex PCR sequence-specific priming, respectively. The allele frequency of HLA-C*08:01 was significantly higher in the CHCs than that of the controls (0.088 vs. 0.040, OR = 2.332, 95%CI: 1.361-3.996, p = 0.022), while the frequencies of B*13:01 (0.032 vs. 0.084, OR = 0.357, 95%CI: 0.204-0.625, p = 0.009) and C*08:04 (0.008 vs. 0.038, OR = 0.214, 95%CI: 0.079-0.581, p = 0.022) were significantly lower in the CHCs. The frequencies of haplotype A*11:01-C*08:01 were higher in the CHCs (0.058 vs. 0.019, OR = 3.096, 95%CI: 1.486-6.452, p = 0.026), while haplotype B*13:01-C*03:04 were lower in the CHCs compared to the controls (0.028 vs. 0.071, OR = 0.377, 95%CI: 0.207-0.685, p = 0.012). No association of CHC with KIR genes, genotypes, or haplotypes, as well as HLA/KIR combinations was observed. Our results indicated that HLA-C*08:01 was a risk factor for CHC, while HLA-C*08:04 and HLA-B*13:01 were protective factors against CHC. Haplotypes HLA-A*11:01-C*08:01 could increase susceptibility to CHC, while HLA-B*13:01-C*03:04 could be protective against CHC in the Chinese Han population.
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Affiliation(s)
- Qiongfen Li
- Division for Expended Program of Immunization of Yunnan Center for Disease Control and Prevention, Kunming, China
| | - Shuyuan Liu
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, China
| | | | - Chengxiu Liu
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, China
| | - Mingbo Sun
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, China
| | - Chuanyin Li
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, China
| | - Xinwen Zhang
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, China
| | - Jun Chen
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, China
| | - Yufeng Yao
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, China
| | - Li Shi
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, China
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21
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Lunemann S, Schöbel A, Kah J, Fittje P, Hölzemer A, Langeneckert AE, Hess LU, Poch T, Martrus G, Garcia-Beltran WF, Körner C, Ziegler AE, Richert L, Oldhafer KJ, Schulze Zur Wiesch J, Schramm C, Dandri M, Herker E, Altfeld M. Interactions Between KIR3DS1 and HLA-F Activate Natural Killer Cells to Control HCV Replication in Cell Culture. Gastroenterology 2018; 155:1366-1371.e3. [PMID: 30031767 DOI: 10.1053/j.gastro.2018.07.019] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Revised: 07/10/2018] [Accepted: 07/14/2018] [Indexed: 12/02/2022]
Abstract
Killer-cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed by natural killer (NK) cells. Binding of KIR3DS1 to its recently discovered ligand, HLA-F, activates NK cells and has been associated with resolution of hepatitis C virus (HCV) infection. We investigated the mechanisms by which KIR3DS1 contributes to the antiviral immune response. Using cell culture systems, mice with humanized livers, and primary liver tissue from HCV-infected individuals, we found that the KIR3DS1 ligand HLA-F is up-regulated on HCV-infected cells, and that interactions between KIR3DS1 and HLA-F contribute to NK cell-mediated control of HCV. Strategies to promote interaction between KIR3DS1 and HLA-F might be developed for treatment of infectious diseases and cancer.
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Affiliation(s)
- Sebastian Lunemann
- Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Anja Schöbel
- Junior Research Group HCV Replication, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Janine Kah
- I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Pia Fittje
- Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Angelique Hölzemer
- Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; I. Department of Medicine, Section Infectious Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Partner site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Annika E Langeneckert
- Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Leonard U Hess
- Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Tobias Poch
- I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Gloria Martrus
- Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; German Center for Infection Research (DZIF), Partner site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | | | - Christian Körner
- Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Annerose E Ziegler
- Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Laura Richert
- Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; INSERM U1219, INRIA SISTM, Bordeaux University, Bordeaux, France
| | - Karl J Oldhafer
- Department of General and Abdominal Surgery, Asklepios Hospital Barmbek, Semmelweis University of Medicine, Asklepios Campus, Hamburg, Germany
| | - Julian Schulze Zur Wiesch
- I. Department of Medicine, Section Infectious Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maura Dandri
- I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eva Herker
- Junior Research Group HCV Replication, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Marcus Altfeld
- Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; German Center for Infection Research (DZIF), Partner site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany; Institute for Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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22
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Kiani Z, Dupuy FP, Bruneau J, Lebouché B, Zhang CX, Jackson E, Lisovsky I, da Fonseca S, Geraghty DE, Bernard NF. HLA-F on HLA-Null 721.221 Cells Activates Primary NK Cells Expressing the Activating Killer Ig-like Receptor KIR3DS1. THE JOURNAL OF IMMUNOLOGY 2018; 201:113-123. [PMID: 29743316 DOI: 10.4049/jimmunol.1701370] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 04/24/2018] [Indexed: 12/21/2022]
Abstract
NK cells elicit important responses against transformed and virally infected cells. Carriage of the gene encoding the activating killer Ig-like receptor KIR3DS1 is associated with slower time to AIDS and protection from HIV infection. Recently, open conformers of the nonclassical MHC class Ib Ag HLA-F were identified as KIR3DS1 ligands. In this study, we investigated whether the interaction of KIR3DS1 on primary NK cells with HLA-F on the HLA-null cell line 721.221 (221) stimulated KIR3DS1+ NK cells. We used a panel of Abs to detect KIR3DS1+CD56dim NK cells that coexpressed the inhibitory NK cell receptors KIR2DL1/L2/L3, 3DL2, NKG2A, and ILT2; the activating NK cell receptors KIR2DS1/S2/S3/S5; and CCL4, IFN-γ, and CD107a functions. We showed that both untreated and acid-pulsed 221 cells induced a similar frequency of KIR3DS1+ cells to secrete CCL4/IFN-γ and express CD107a with a similar intensity. A higher percentage of KIR3DS1+ than KIR3DS1- NK cells responded to 221 cells when either inclusive or exclusive (i.e., coexpressing none of the other inhibitory NK cell receptors and activating NK cell receptors detected by the Ab panel) gating strategies were employed to identify these NK cell populations. Blocking the interaction of HLA-F on 221 cells with KIR3DS1-Fc chimeric protein or anti-HLA-F Abs on exclusively gated KIR3DS1+ cells reduced the frequency of functional cells compared with that of unblocked conditions for stimulated KIR3DS1+ NK cells. Thus, ligation of KIR3DS1 activates primary NK cells for several antiviral functions.
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Affiliation(s)
- Zahra Kiani
- Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.,Division of Experimental Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada
| | - Franck P Dupuy
- Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada
| | - Julie Bruneau
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H2X 0A9, Canada.,Department of Family Medicine, University of Montreal, Montreal, Quebec H3T 1J4, Canada
| | - Bertrand Lebouché
- Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.,Chronic Viral Illness Service, McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.,Department of Family Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada
| | - Cindy X Zhang
- Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.,Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada
| | - Elise Jackson
- Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.,Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada
| | - Irene Lisovsky
- Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.,Division of Experimental Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada
| | - Sandrina da Fonseca
- Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada
| | - Daniel E Geraghty
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; and
| | - Nicole F Bernard
- Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada; .,Division of Experimental Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada.,Chronic Viral Illness Service, McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.,Division of Clinical Immunology, McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada
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23
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Walker AJ, Peacock CJ, Pedergnana V, Irving WL. Host genetic factors associated with hepatocellular carcinoma in patients with hepatitis C virus infection: A systematic review. J Viral Hepat 2018; 25:442-456. [PMID: 29397014 PMCID: PMC6321980 DOI: 10.1111/jvh.12871] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 01/02/2018] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV)-infected patients are at risk of developing hepatocellular carcinoma (HCC). Individuals at heightened risk could be targeted by intensive follow-up surveillance. We have conducted a systematic review of the literature to identify host genetic predisposition to HCC in HCV-infected patients. A comprehensive search of Medline and Embase databases was performed, and the strength of evidence of associations for each gene on development of HCC was evaluated. We identified 166 relevant studies, relating to 137 different genes, or combinations thereof. Seventeen genes were classified as having "good" evidence of an association, a significant association was observed for 37 genes but this finding had not yet been replicated, 56 genes had mixed or limited evidence of an association, and 27 genes showed no association. IFNL3/4, TNF-α and PNPLA3 genes had the most evidence of an association. There was, however, considerable heterogeneity in study design and data quality. In conclusion, we identified a number of genes with evidence of association with HCC, but also a need for more standardized approaches to address this clinically critical question. It is important to consider the underlying mechanism of these relationships and which are confounded by the presence of other HCC risk factors and response to therapy. We also identified many genes where the evidence of association is contradictory or requires replication, as well as a number where associations have been studied but no evidence found. These findings should help to direct future studies on host genetic predisposition to HCC in HCV-infected patients.
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Affiliation(s)
- A. J. Walker
- National Institute for Health research (NIHR) Nottingham Biomedical Research CentreNottingham University Hospitals NHS TrustUniversity of NottinghamNottinghamUK,Centre for Evidence Based MedicineDepartment of Primary Care Health SciencesUniversity of OxfordOxfordUK
| | - C. J. Peacock
- National Institute for Health research (NIHR) Nottingham Biomedical Research CentreNottingham University Hospitals NHS TrustUniversity of NottinghamNottinghamUK
| | - V. Pedergnana
- Wellcome Trust Centre for Human GeneticsUniversity of OxfordOxfordUK
| | | | - W. L. Irving
- National Institute for Health research (NIHR) Nottingham Biomedical Research CentreNottingham University Hospitals NHS TrustUniversity of NottinghamNottinghamUK
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24
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Kared H, Martelli S, Tan SW, Simoni Y, Chong ML, Yap SH, Newell EW, Pender SLF, Kamarulzaman A, Rajasuriar R, Larbi A. Adaptive NKG2C +CD57 + Natural Killer Cell and Tim-3 Expression During Viral Infections. Front Immunol 2018; 9:686. [PMID: 29731749 PMCID: PMC5919961 DOI: 10.3389/fimmu.2018.00686] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 03/20/2018] [Indexed: 12/13/2022] Open
Abstract
Repetitive stimulation by persistent pathogens such as human cytomegalovirus (HCMV) or human immunodeficiency virus (HIV) induces the differentiation of natural killer (NK) cells. This maturation pathway is characterized by the acquisition of phenotypic markers, CD2, CD57, and NKG2C, and effector functions—a process regulated by Tim-3 and orchestrated by a complex network of transcriptional factors, involving T-bet, Eomes, Zeb2, promyelocytic leukemia zinc finger protein, and Foxo3. Here, we show that persistent immune activation during chronic viral co-infections (HCMV, hepatitis C virus, and HIV) interferes with the functional phenotype of NK cells by modulating the Tim-3 pathway; a decrease in Tim-3 expression combined with the acquisition of inhibitory receptors skewed NK cells toward an exhausted and cytotoxic phenotype in an inflammatory environment during chronic HIV infection. A better understanding of the mechanisms underlying NK cell differentiation could aid the identification of new immunological targets for checkpoint blockade therapies in a manner that is relevant to chronic infection and cancer.
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Affiliation(s)
- Hassen Kared
- Singapore Immunology Network (SIgN), Aging and Immunity Program, Agency for Science Technology and Research (ASTAR), Singapore, Singapore
| | - Serena Martelli
- Singapore Immunology Network (SIgN), Aging and Immunity Program, Agency for Science Technology and Research (ASTAR), Singapore, Singapore.,Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Shu Wen Tan
- Singapore Immunology Network (SIgN), Aging and Immunity Program, Agency for Science Technology and Research (ASTAR), Singapore, Singapore
| | - Yannick Simoni
- Singapore Immunology Network (SIgN), Aging and Immunity Program, Agency for Science Technology and Research (ASTAR), Singapore, Singapore
| | - Meng Li Chong
- Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia
| | - Siew Hwei Yap
- Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia
| | - Evan W Newell
- Singapore Immunology Network (SIgN), Aging and Immunity Program, Agency for Science Technology and Research (ASTAR), Singapore, Singapore
| | - Sylvia L F Pender
- Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Adeeba Kamarulzaman
- Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia.,Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Reena Rajasuriar
- Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia.,Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.,The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
| | - Anis Larbi
- Singapore Immunology Network (SIgN), Aging and Immunity Program, Agency for Science Technology and Research (ASTAR), Singapore, Singapore.,Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
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25
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Saito H, Umemura T, Joshita S, Yamazaki T, Fujimori N, Kimura T, Komatsu M, Matsumoto A, Tanaka E, Ota M. KIR2DL2 combined with HLA-C1 confers risk of hepatitis C virus-related hepatocellular carcinoma in younger patients. Oncotarget 2018; 9:19650-19661. [PMID: 29731972 PMCID: PMC5929415 DOI: 10.18632/oncotarget.24752] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 03/06/2018] [Indexed: 01/17/2023] Open
Abstract
Killer cell immunoglobulin-like receptors (KIRs) are involved in the activation and inhibition of natural killer cells. Although combinations of KIRs and HLA have been associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection, their roles are not fully understood in the context of hepatocellular carcinoma (HCC) development. We enrolled 787 consecutive patients with chronic HCV infection, which included 174 cases of HCC, and 325 healthy subjects to clarify the involvement of HLA-Bw and C, KIRs, and major histocompatibility complex class I chain-related gene A (MICA) gene polymorphisms (rs2596542 and rs1051792) in chronic HCV infection and HCV-related HCC. We observed a significant association with chronic hepatitis C susceptibility for HLA-Bw4 (P = 0.00012; odds ratio [OR] = 1.66) and significant protective associations for HLA-C2 and KIR2DL1-HLA-C2 (both P = 0.00099; OR = 0.57). When HCC patients were stratified into younger (<65 years) and older (≥65 years) groups, the frequencies of KIR2DL2-HLA-C1 and KIR2DS2-HLA-C1 (P = 0.008; OR = 2.89 and P = 0.015; OR = 2.79, respectively) as well as rs2596542 and rs1051792 (P = 0.020; OR = 2.17 and P = 0.038; OR = 2.01, respectively) were significantly higher in younger patients. KIR2DL2-HLA-C1 (OR = 2.75; 95% confidence interval: 1.21-6.21, P = 0.015) and rs1051792 (OR = 2.48; 95% confidence interval: 1.23-4.98, P = 0.011) were independently associated with HCC development in younger patients. These results suggest that KIR2DL2-HLA-C1 and rs1051792 may represent molecular biomarkers to identify early onset HCV-related HCC.
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Affiliation(s)
- Hiromi Saito
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.,Research Center for Next Generation Medicine, Shinshu University, Matsumoto, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.,Research Center for Next Generation Medicine, Shinshu University, Matsumoto, Japan
| | - Tomoo Yamazaki
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Naoyuki Fujimori
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takefumi Kimura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Michiharu Komatsu
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akihiro Matsumoto
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Eiji Tanaka
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Masao Ota
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
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26
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Yindom LM, Mendy M, Bodimeade C, Chambion C, Aka P, Whittle HC, Rowland-Jones SL, Walton R. KIR content genotypes associate with carriage of hepatitis B surface antigen, e antigen and HBV viral load in Gambians. PLoS One 2017; 12:e0188307. [PMID: 29149205 PMCID: PMC5693433 DOI: 10.1371/journal.pone.0188307] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2017] [Accepted: 11/04/2017] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) causes over 800,000 deaths worldwide annually, mainly in low income countries, and incidence is rising rapidly in the developed world with the spread of hepatitis B (HBV) and C (HCV) viruses. Natural Killer (NK) cells protect against viral infections and tumours by killing abnormal cells recognised by Killer-cell Immunoglobulin-like Receptors (KIR). Thus genes and haplotypes encoding these receptors may be important in determining both outcome of initial hepatitis infection and subsequent chronic liver disease and tumour formation. HBV is highly prevalent in The Gambia and the commonest cause of liver disease. The Gambia Liver Cancer Study was a matched case-control study conducted between September 1997 and January 2001 where cases with liver disease were identified in three tertiary referral hospitals and matched with out-patient controls with no clinical evidence of liver disease. METHODS We typed 15 KIR genes using the polymerase chain reaction with sequence specific primers (PCR-SSP) in 279 adult Gambians, 136 with liver disease (HCC or Cirrhosis) and 143 matched controls. We investigated effects of KIR genotypes and haplotypes on HBV infection and associations with cirrhosis and HCC. RESULTS Homozygosity for KIR group A gene-content haplotype was associated with HBsAg carriage (OR 3.7, 95% CI 1.4-10.0) whilst telomeric A genotype (t-AA) was associated with reduced risk of e antigenaemia (OR 0.2, 95% CI 0.0-0.6) and lower viral loads (mean log viral load 5.2 vs. 6.9, pc = 0.022). One novel telomeric B genotype (t-ABx2) containing KIR3DS1 (which is rare in West Africa) was also linked to e antigenaemia (OR 8.8, 95% CI 1.3-60.5). There were no associations with cirrhosis or HCC. CONCLUSION Certain KIR profiles may promote clearance of hepatitis B surface antigen whilst others predispose to e antigen carriage and high viral load. Larger studies are necessary to quantify the effects of individual KIR genes, haplotypes and KIR/HLA combinations on long-term viral carriage and risk of liver cancer. KIR status could potentially inform antiviral therapy and identify those at increased risk of complications for enhanced surveillance.
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MESH Headings
- Adult
- Carcinoma, Hepatocellular/complications
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Case-Control Studies
- Chromosomes, Human, Pair 19/chemistry
- Female
- Gambia
- Gene Expression
- Genotype
- Hepatitis B Surface Antigens/genetics
- Hepatitis B Surface Antigens/immunology
- Hepatitis B e Antigens/genetics
- Hepatitis B e Antigens/immunology
- Hepatitis B virus/genetics
- Hepatitis B virus/immunology
- Hepatitis B virus/pathogenicity
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/genetics
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/pathology
- Humans
- Killer Cells, Natural/immunology
- Killer Cells, Natural/pathology
- Liver Cirrhosis/complications
- Liver Cirrhosis/genetics
- Liver Cirrhosis/immunology
- Liver Cirrhosis/pathology
- Liver Neoplasms/complications
- Liver Neoplasms/genetics
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Male
- Receptors, KIR/classification
- Receptors, KIR/genetics
- Receptors, KIR/immunology
- Tertiary Care Centers
- Viral Load/genetics
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Affiliation(s)
- Louis-Marie Yindom
- University of Oxford, Nuffield Department of Medicine, Oxford, United Kingdom
- Medical Research Council (UK), Fajara, The Gambia
| | - Maimuna Mendy
- Medical Research Council (UK), Fajara, The Gambia
- International Agency for Research on Cancer, Lyon, France
| | | | | | - Peter Aka
- Medical Research Council (UK), Fajara, The Gambia
- Demographic and Health Surveys, ICF International, Rockville, Maryland United States of America
| | - Hilton C. Whittle
- Medical Research Council (UK), Fajara, The Gambia
- London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Sarah L. Rowland-Jones
- University of Oxford, Nuffield Department of Medicine, Oxford, United Kingdom
- Medical Research Council (UK), Fajara, The Gambia
| | - Robert Walton
- Warwick Medical School, University of Warwick, Coventry, United Kingdom
- Centre for Primary Care and Public Health, Barts and the London School of Medicine and Dentistry, Queen Mary University, London, United Kingdom
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27
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Li W, Shen X, Fu B, Guo C, Liu Y, Ye Y, Sun R, Li J, Tian Z, Wei H. KIR3DS1/HLA-B Bw4-80Ile Genotype Is Correlated with the IFN-α Therapy Response in hepatitis B e antigen-Positive Chronic Hepatitis B. Front Immunol 2017; 8:1285. [PMID: 29075265 PMCID: PMC5641573 DOI: 10.3389/fimmu.2017.01285] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 09/25/2017] [Indexed: 12/17/2022] Open
Abstract
To date, several on-treatment-level virological and serological indices that may predict the response to interferon alpha (IFN-α) have been reported. However, no effective predictors, such as drug–response genes, that can be detected before administration of anti-hepatitis B virus (HBV) therapy with IFN-α, have been found. In the diverse range of chronic viral infection, genes that affect human immunity play important roles in understanding host and viral co-evolution. Killer-cell immunoglobulin-like receptors (KIRs), which are highly polymorphic at the allele and haplotype levels, participate in the antiviral function of natural killer (NK) cells via fine-tuning inhibition and activation of NK-cell responses that occur when the NK cells interact with human leukocyte antigen (HLA) class I molecules on target cells. For each individual, the pairing of KIR and HLA ligand is genetically determined. To investigate whether a particular KIR and HLA repertoire influences the risk of HBV infection and response to IFN-α treatment for chronic hepatitis B (CHB), we genotyped the KIRs and HLA ligands of 119 hepatitis B e antigen (HBeAg)-positive CHB patients. These patients included 43 patients who achieved sustained response (SR) induced by IFN-α treatment for 48 weeks, 76 patients who achieved no response (NR), and 96 healthy subjects as controls. SR was defined as HBeAg loss with HBV DNA < 2,000 IU/ml and alanine aminotransferase normalization at 24 weeks posttreatment (week 72). In this study, we showed that activating KIR genes were less prevalent in Han Chinese, especially in Han Chinese with CHB, than in Caucasians. Furthermore, the KIR3DS1 gene, in combination with HLA-B Bw4-80Ile, strongly influenced the therapeutic outcomes for CHB patients who were treated with IFN-α. The frequency of the combination of genes encoding KIR3DS1 and HLA-B Bw4-80Ile was higher in patients who had a sustained treatment response than in patients who had NR [35.3 versus 1.3%; odds ratio (OR) = 19.85; P = 0.0008]. Activating KIR3DS1 and HLA-B Bw4-80Ile synergistically predicted SR to IFN-α for HBeAg-positive CHB patients. Genotyping for the KIR3DS1 gene and the HLA-B Bw4-80Ile allele might help physicians choose the optimal candidates for anti-HBV treatment with IFN-α.
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Affiliation(s)
- Wenting Li
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Xiaokun Shen
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Binqing Fu
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Institute of Immunology, 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
| | - Chuang Guo
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Yanyan Liu
- Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ying Ye
- Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Rui Sun
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Institute of Immunology, 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
| | - Jiabin Li
- Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhigang Tian
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Institute of Immunology, 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
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Institute of Immunology, 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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Prakash S, Sarangi AN, Alam S, Sonawane A, Sharma RK, Agrawal S. Putative role of KIR3DL1/3DS1 alleles and HLA-Bw4 ligands with end stage renal disease and long term renal allograft survival. Gene 2017; 637:219-229. [PMID: 28942035 DOI: 10.1016/j.gene.2017.09.033] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 09/19/2017] [Indexed: 12/31/2022]
Abstract
BACKGROUND Killer immunoglobulin receptors (KIR) are highly polymorphic in nature. KIR3DL1/3DS1 genes are known to affect HLA-B antigen binding affinity causing natural killer (NK) cell inhibition, which results into successful renal transplantation. In this study we have examined whether alleles of KIR3DL1/3DS1 play any role in changing the binding affinity with HLA-Bw4 antigen and if so then how are they associated with long term renal allograft survival. We have also evaluated plausible association of KIR3DL1 with HLA-A23/A24/A32 with renal pathophysiology. MATERIALS AND METHODS KIR3DL1/3DS1 allelic diversity was examined in 501 renal transplant cases and 507 controls. PCR-SSP was used to determine the incidence of KIR3DL1/3DS1 genes and HLA class-I antigens. KIR3DL1/3DS1 alleles were determined by sequencing. Expression at transcription level for KIR3DL1/3DS1 genes was evaluated in the presence of HLA-Bw4. Different statistical analyses were performed using SPSS v 22.0. p≤0.05 was considered significant. Sequence based variant effect was predicted using Variant Effect Predictor. To evaluate whether variation in KIR3DL1 and HLA interaction changes the binding affinity structure based effect prediction was carried out using MutaBind and BindProf software. RESULTS For KIR3DL1*0010101, no-risk and low mRNA expression was seen among antibody mediated acute rejection (ABMR) and chronic rejection (CR) cases. Whereas, 3DS1*01301, 3DL1*00401, and 3DL1*00402 showed susceptibility and elevated mRNA expression with ABMR and CR. Two mutations c.320C>T (rs143159382) and c.911G>T (rs35974949), present in alleles 3DL1*00402 and 3DL1*00401 were predicted to be deleterious. Reduced renal allograft survival was observed for individuals possessing KIR3DL1*00401-HLA-Bw4+. In relation to HLA-A locus no significance was observed with ESRD, ABMR, and CR. DISCUSSION The experimental and computational data corroborated with each other suggesting susceptibility for renal allograft in presence of 3DL1*00402 and 3DL1*00401 alleles.
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Affiliation(s)
- Swayam Prakash
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh, India
| | - Aditya Narayan Sarangi
- Biomedical Informatics Centre, School of Telemedicine and Biomedical Informatics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh, India
| | - Shahnawaz Alam
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh, India
| | - Avinash Sonawane
- School of Biotechnology, Kalinga Institute of Industrial Technology University, Bhubaneswar, Odisha, India
| | - Raj Kumar Sharma
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh, India
| | - Suraksha Agrawal
- Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh, India.
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Carlomagno S, Falco M, Bono M, Alicata C, Garbarino L, Mazzocco M, Moretta L, Moretta A, Sivori S. KIR3DS1-Mediated Recognition of HLA-*B51: Modulation of KIR3DS1 Responsiveness by Self HLA-B Allotypes and Effect on NK Cell Licensing. Front Immunol 2017; 8:581. [PMID: 28603523 PMCID: PMC5445109 DOI: 10.3389/fimmu.2017.00581] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 05/01/2017] [Indexed: 12/24/2022] Open
Abstract
Several studies described an association between killer-cell immunoglobulin-like receptor (KIR)/HLA gene combinations and clinical outcomes in various diseases. In particular, an important combined role for KIR3DS1 and HLA-B Bw4-I80 in controlling viral infections and a higher protection against leukemic relapses in donor equipped with activating KIRs in haplo-HSCT has been described. Here, we show that KIR3DS1 mediates positive signals upon recognition of HLA-B*51 (Bw4-I80) surface molecules on target cells and that this activation occurs only in Bw4-I80neg individuals, including those carrying particular KIR/HLA combination settings. In addition, killing of HLA-B*51 transfected target cells mediated by KIR3DS1+/NKG2A+ natural killer (NK) cell clones from Bw4-I80neg donors could be partially inhibited by antibody-mediated masking of KIR3DS1. Interestingly, KIR3DS1-mediated recognition of HLA-B*51 could be better appreciated under experimental conditions in which the function of NKG2D was reduced by mAb-mediated blocking. This experimental approach may mimic the compromised function of NKG2D occurring in certain viral infections. We also show that, in KIR3DS1+/NKG2A+ NK cell clones derived from an HLA-B Bw4-T80 donor carrying 2 KIR3DS1 gene copy numbers, the positive signal generated by the engagement of KIR3DS1 by HLA-B*51 resulted in a more efficient killing of HLA-B*51-transfected target cells. Moreover, in these clones, a direct correlation between KIR3DS1 and NKG2D surface density was detected, while the expression of NKp46 was inversely correlated with that of KIR3DS1. Finally, we analyzed KIR3DS1+/NKG2A+ NK cell clones from a HLA-B Bw4neg donor carrying cytoplasmic KIR3DL1. Although these clones expressed lower levels of surface KIR3DS1, they displayed responses comparable to those of NK cell clones derived from HLA-B Bw4neg donors that expressed surface KIR3DL1. Altogether these data suggest that, in particular KIR/HLA combinations, KIR3DS1 may play a role in the process of human NK cell education.
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Affiliation(s)
- Simona Carlomagno
- Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy
| | | | - Maria Bono
- Istituto Giannina Gaslini, Genova, Italy
| | - Claudia Alicata
- Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy.,Centro di Eccellenza per le Ricerche Biomediche, Università degli Studi di Genova, Genova, Italy
| | - Lucia Garbarino
- S.C. Laboratorio di Istocompatibilità e IBMDR, E.O. Ospedali Galliera, Genova, Italy
| | - Michela Mazzocco
- S.C. Laboratorio di Istocompatibilità e IBMDR, E.O. Ospedali Galliera, Genova, Italy
| | - Lorenzo Moretta
- Dipartimento di Immunologia, IRCCS Ospedale Bambin Gesù, Roma, Italy
| | - Alessandro Moretta
- Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy.,Centro di Eccellenza per le Ricerche Biomediche, Università degli Studi di Genova, Genova, Italy
| | - Simona Sivori
- Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy.,Centro di Eccellenza per le Ricerche Biomediche, Università degli Studi di Genova, Genova, Italy
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30
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Ocular toxoplasmosis: susceptibility in respect to the genes encoding the KIR receptors and their HLA class I ligands. Sci Rep 2016; 6:36632. [PMID: 27827450 PMCID: PMC5101474 DOI: 10.1038/srep36632] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 10/17/2016] [Indexed: 11/24/2022] Open
Abstract
The objective of this study was to investigate the influence of the genes encoding the KIR receptors and their HLA ligands in the susceptibility of ocular toxoplasmosis. A total of 297 patients serologically-diagnosed with toxoplasmosis were selected and stratified according to the presence (n = 148) or absence (n = 149) of ocular scars/lesions due to toxoplasmosis. The group of patients with scars/lesions was further subdivided into two groups according to the type of ocular manifestation observed: primary (n = 120) or recurrent (n = 28). Genotyping was performed by PCR-SSOP. Statistical analyses were conducted using the Chi-square test, and odds ratio with a 95% confidence interval was also calculated to evaluate the risk association. The activating KIR3DS1 gene was associated with increased susceptibility for ocular toxoplasmosis. The activating KIR together with their HLA ligands (KIR3DS1-Bw4-80Ile and KIR2DS1+/C2++ KIR3DS1+/Bw4-80Ile+) were associated with increased susceptibility for ocular toxoplasmosis and its clinical manifestations. KIR-HLA inhibitory pairs -KIR2DL3/2DL3-C1/C1 and KIR2DL3/2DL3-C1- were associated with decreased susceptibility for ocular toxoplasmosis and its clinical forms, while the KIR3DS1−/KIR3DL1+/Bw4-80Ile+ combination was associated as a protective factor against the development of ocular toxoplasmosis and, in particular, against recurrent manifestations. Our data demonstrate that activating and inhibitory KIR genes may influence the development of ocular toxoplasmosis.
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31
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Garcia-Beltran WF, Hölzemer A, Martrus G, Chung AW, Pacheco Y, Simoneau CR, Rucevic M, Lamothe-Molina PA, Pertel T, Kim TE, Dugan H, Alter G, Dechanet-Merville J, Jost S, Carrington M, Altfeld M. Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1. Nat Immunol 2016; 17:1067-74. [PMID: 27455421 PMCID: PMC4992421 DOI: 10.1038/ni.3513] [Citation(s) in RCA: 167] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 06/13/2016] [Indexed: 12/23/2022]
Abstract
The activating natural killer (NK)-cell receptor KIR3DS1 has been linked to the outcome of various human diseases, including delayed progression of disease caused by human immunodeficiency virus type 1 (HIV-1), yet a ligand that would account for its biological effects has remained unknown. We screened 100 HLA class I proteins and found that KIR3DS1 bound to HLA-F, a result we confirmed biochemically and functionally. Primary human KIR3DS1(+) NK cells degranulated and produced antiviral cytokines after encountering HLA-F and inhibited HIV-1 replication in vitro. Activation of CD4(+) T cells triggered the transcription and surface expression of HLA-F mRNA and HLA-F protein, respectively, and induced binding of KIR3DS1. HIV-1 infection further increased the transcription of HLA-F mRNA but decreased the binding of KIR3DS1, indicative of a mechanism for evading recognition by KIR3DS1(+) NK cells. Thus, we have established HLA-F as a ligand of KIR3DS1 and have demonstrated cell-context-dependent expression of HLA-F that might explain the widespread influence of KIR3DS1 in human disease.
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Affiliation(s)
| | - Angelique Hölzemer
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA
- Heinrich-Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
- First Department of Internal Medicine, University Medical Centre Eppendorf, Hamburg, Germany
| | - Gloria Martrus
- Heinrich-Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Amy W. Chung
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA
| | - Yovana Pacheco
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA
- Departamento de Matemáticas, Facultad de Ciencias, Universidad Nuestra Señora del Rosario, Bogotá, Colombia
| | | | | | | | - Thomas Pertel
- Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Tae-Eun Kim
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA
| | - Haley Dugan
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA
| | - Galit Alter
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA
| | | | | | - Mary Carrington
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA
- Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Marcus Altfeld
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA
- Heinrich-Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
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32
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Forlenza CJ, Boudreau JE, Zheng J, Le Luduec JB, Chamberlain E, Heller G, Cheung NKV, Hsu KC. KIR3DL1 Allelic Polymorphism and HLA-B Epitopes Modulate Response to Anti-GD2 Monoclonal Antibody in Patients With Neuroblastoma. J Clin Oncol 2016; 34:2443-51. [PMID: 27069083 DOI: 10.1200/jco.2015.64.9558] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
PURPOSE In patients with neuroblastoma (NB), treatment with anti-GD2 monoclonal antibody (mAb) directs natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against tumor cells. However, tumor cytotoxicity is attenuated by ligation of inhibitory killer immunoglobulin-like receptors (KIRs) by HLA class I molecules. KIR3DL1 polymorphism influences its ability to engage HLA-Bw4 ligands. We tested the hypothesis that poorly interacting combinations of KIR3DL1 and HLA ligands are more permissive of mAb-mediated antitumor effect. METHODS KIR3DL1 and HLA-B subtyping were performed with a multiplex intermediate-resolution polymerase chain reaction assay for a cohort of 245 patients who were treated with antibody 3F8 for high-risk NB. Patient outcomes were analyzed according to expected degree of interaction between KIR3DL1 and HLA-B subtypes and grouped as strong, weak, or noninteractors. A comparison of NK response to 3F8 mAb opsonized NB cells between strong- and noninteracting donors was performed by flow cytometry. RESULTS KIR3DL1 and HLA-B subtype combinations associated with noninteraction as a result of lack of receptor expression [KIR3DL1(-)], failure of interaction with inhibitory ligands [KIR3DS1(+)], or absence of KIR ligands resulted in significantly improved overall and progression-free survival. Patients with KIR3DL1 and HLA-B subtype combinations that were predictive of weak interaction had superior outcomes compared with those that were predictive of strong interaction; however, both groups were inferior to those with noninteracting subtype combinations. In vitro analysis of 3F8-mediated ADCC showed that KIR3DL1(-) and 3DS1(+) NK cells were insensitive to inhibition by HLA-Bw4-expressing NB targets. CONCLUSION We conclude that KIR3LD1 and HLA-B allele combinations can have a prognostic impact on patient survival after treatment with anti-GD2 mAb that relies on NK-ADCC. The survival advantage seen in noninteracting combinations supports the therapeutic disinhibition of individuals with strongly interacting KIR and ligand pairs.
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Affiliation(s)
- Christopher J Forlenza
- Christopher J. Forlenza, Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu, Memorial Sloan Kettering Cancer Center; and Katharine C. Hsu, Weill Cornell Medical College, New York, NY
| | - Jeanette E Boudreau
- Christopher J. Forlenza, Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu, Memorial Sloan Kettering Cancer Center; and Katharine C. Hsu, Weill Cornell Medical College, New York, NY
| | - Junting Zheng
- Christopher J. Forlenza, Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu, Memorial Sloan Kettering Cancer Center; and Katharine C. Hsu, Weill Cornell Medical College, New York, NY
| | - Jean-Benoît Le Luduec
- Christopher J. Forlenza, Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu, Memorial Sloan Kettering Cancer Center; and Katharine C. Hsu, Weill Cornell Medical College, New York, NY
| | - Elizabeth Chamberlain
- Christopher J. Forlenza, Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu, Memorial Sloan Kettering Cancer Center; and Katharine C. Hsu, Weill Cornell Medical College, New York, NY
| | - Glenn Heller
- Christopher J. Forlenza, Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu, Memorial Sloan Kettering Cancer Center; and Katharine C. Hsu, Weill Cornell Medical College, New York, NY
| | - Nai-Kong V Cheung
- Christopher J. Forlenza, Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu, Memorial Sloan Kettering Cancer Center; and Katharine C. Hsu, Weill Cornell Medical College, New York, NY
| | - Katharine C Hsu
- Christopher J. Forlenza, Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu, Memorial Sloan Kettering Cancer Center; and Katharine C. Hsu, Weill Cornell Medical College, New York, NY.
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33
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Vineretsky KA, Karagas MR, Christensen BC, Kuriger-Laber JK, Perry AE, Storm CA, Nelson HH. Skin Cancer Risk Is Modified by KIR/HLA Interactions That Influence the Activation of Natural Killer Immune Cells. Cancer Res 2016; 76:370-6. [PMID: 26744525 DOI: 10.1158/0008-5472.can-15-0547] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 10/21/2015] [Indexed: 11/16/2022]
Abstract
Natural killer (NK)-cell phenotype is partially mediated through binding of killer-cell immunoglobulin-like receptors (KIR) with HLA class I ligands. The KIR gene family is highly polymorphic and not well captured by standard genome-wide association study approaches. Here, we tested the hypothesis that variations in KIR gene content combined with HLA class I ligand status is associated with keratinocyte skin cancers using a population-based study of basal cell carcinoma (BCC) and squamous cell carcinomas (SCC). We conducted an interaction analysis of KIR gene content variation and HLA-B (Bw4 vs. Bw6) and HLA-C (C1 vs. C2). KIR centromeric B haplotype was associated with significant risk of multiple BCC tumors (OR, 2.39; 95% confidence interval, 1.10-5.21), and there was a significant interaction between HLA-C and the activating gene KIR2DS3 for BCC (Pinteraction = 0.005). Furthermore, there was significant interaction between HLA-B and telomeric KIR B haplotype (containing the activating genes KIR3DS1 and KIR2DS1) as well as HLA-B and the activating KIR gene KIR2DS5 (Pinteraction 0.001 and 0.012, respectively). Similar but greatly attenuated associations were observed for SCC. Moreover, previous in vitro models demonstrated that p53 is required for upregulation of NK ligands, and accordingly, we observed there was a strong association between the KIR B haplotype and p53 alteration in BCC tumors, with a higher likelihood that KIR B carriers harbor abnormal p53 (P < 0.004). Taken together, our data suggest that functional interactions between KIR and HLA modify risks of BCC and SCC and that KIR encoded by the B genes provides selective pressure for altered p53 in BCC tumors.
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Affiliation(s)
- Karin A Vineretsky
- Division of Environmental Health Sciences, School of Public Health, University of Minnesota, Minneapolis, Minnesota
| | - Margaret R Karagas
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
| | - Brock C Christensen
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
| | | | - Ann E Perry
- Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
| | - Craig A Storm
- Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
| | - Heather H Nelson
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
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Della Chiesa M, Sivori S, Carlomagno S, Moretta L, Moretta A. Activating KIRs and NKG2C in Viral Infections: Toward NK Cell Memory? Front Immunol 2015; 6:573. [PMID: 26617607 PMCID: PMC4638145 DOI: 10.3389/fimmu.2015.00573] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 10/26/2015] [Indexed: 01/27/2023] Open
Abstract
Natural killer (NK) cells are important players in the immune defense against viral infections. The contribution of activating killer immunoglobulin-like receptors (KIRs) and CD94/NKG2C in regulating anti-viral responses has recently emerged. Thus, in the hematopoietic stem cell transplantation setting, the presence of donor activating KIRs (aKIRs) may protect against viral infections, while in HIV-infected individuals, KIR3DS1, in combination with HLA-Bw4-I80, results in reduction of viral progression. Since, studies have been performed mainly at the genetic or transcriptional level, the effective size, the function, and the "licensing" status of NK cells expressing aKIRs, as well as the nature of their viral ligands, require further investigation. Certain viral infections, mainly due to Human cytomegalovirus (HCMV), can deeply influence the NK cell development and function by inducing a marked expansion of mature NKG2C(+) NK cells expressing self-activating KIRs. This suggests that NKG2C and/or aKIRs are involved in the selective proliferation of this subset. The persistent, HCMV-induced, imprinting suggests that NK cells may display unexpected adaptive immune traits. The role of aKIRs and NKG2C in regulating NK cell responses and promoting a memory-like response to certain viruses is discussed.
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Affiliation(s)
- Mariella Della Chiesa
- Dipartimento di Medicina Sperimentale and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova , Genoa , Italy
| | - Simona Sivori
- Dipartimento di Medicina Sperimentale and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova , Genoa , Italy
| | - Simona Carlomagno
- Dipartimento di Medicina Sperimentale and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova , Genoa , Italy
| | - Lorenzo Moretta
- Dipartimento di Immunologia, IRCCS Ospedale Bambin Gesù , Roma , Italy
| | - Alessandro Moretta
- Dipartimento di Medicina Sperimentale and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova , Genoa , Italy
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Deng Z, Zhen J, Zhu B, Zhang G, Yu Q, Wang D, Xu Y, He L, Lu L. Allelic diversity of KIR3DL1/3DS1 in a southern Chinese population. Hum Immunol 2015; 76:663-6. [PMID: 26416088 DOI: 10.1016/j.humimm.2015.09.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Revised: 08/14/2015] [Accepted: 09/25/2015] [Indexed: 11/25/2022]
Abstract
The inhibitory KIR3DL1 and the activating KIR3DS1 segregate as alleles of the same locus. KIR3DL1 is highly diversified at the allele level and KIR3DL1 alleles exhibit varied levels of expression and ligand binding affinity resulting in varied degrees of NK cell inhibition. Previous studies have shown that the KIR3DL1/3DS1 polymorphism associated with viral infection, cancer and transplantation. However, little is known about the population distribution of KIR3DL1/3DS1 alleles in Chinese. The present study examined allelic diversity of KIR3DL1/3DS1 in a southern Chinese population (N=306) using PCR-SSP and sequencing based typing. The presence of KIR3DL1 and KIR3DS1 were detected in 97.1% and 34.0% of the tested individuals respectively. A total of 10 KIR3DL1 alleles (including 2 novel ones) and 6 KIR3DS1 alleles (including 5 novel ones) were identified. Common KIR3DL1 alleles (>10%) were KIR3DL1*01502 (74.8%), KIR3DL1*00501 (23.9%) and KIR3DL1*00701 (15.7%). KIR3DS1*01301 was the predominant KIR3DS1 allele with other KIR3DS1 alleles only sporadically observed. The knowledge of the allelic polymorphism of KIR3DL1/3DS1 may help to better understand the role played by KIR3DL1/3DS1 in associated diseases and clinical transplantation in southern Chinese.
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Affiliation(s)
- Zhihui Deng
- Immunogenetics Laboratory, Shenzhen Blood Center, Shenzhen, Guangdong 518035, China.
| | - Jianxin Zhen
- Immunogenetics Laboratory, Shenzhen Blood Center, Shenzhen, Guangdong 518035, China.
| | - Bofeng Zhu
- College of Medicine, Xi'An Jiaotong University, Xi'an, Shaanxi 710049, China.
| | - Guobing Zhang
- Immunogenetics Laboratory, Shenzhen Blood Center, Shenzhen, Guangdong 518035, China.
| | - Qiong Yu
- Immunogenetics Laboratory, Shenzhen Blood Center, Shenzhen, Guangdong 518035, China.
| | - Daming Wang
- Immunogenetics Laboratory, Shenzhen Blood Center, Shenzhen, Guangdong 518035, China.
| | - Yunping Xu
- Immunogenetics Laboratory, Shenzhen Blood Center, Shenzhen, Guangdong 518035, China.
| | - Liumei He
- Immunogenetics Laboratory, Shenzhen Blood Center, Shenzhen, Guangdong 518035, China.
| | - Liang Lu
- Immunogenetics Laboratory, Shenzhen Blood Center, Shenzhen, Guangdong 518035, China.
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Abstract
Natural killer (NK) cells are immune cells that play a crucial role against viral infections and tumors. To be tolerant against healthy tissue and simultaneously attack infected cells, the activity of NK cells is tightly regulated by a sophisticated array of germline-encoded activating and inhibiting receptors. The best characterized mechanism of NK cell activation is “missing self” detection, i.e., the recognition of virally infected or transformed cells that reduce their MHC expression to evade cytotoxic T cells. To monitor the expression of MHC-I on target cells, NK cells have monomorphic inhibitory receptors which interact with conserved MHC molecules. However, there are other NK cell receptors (NKRs) encoded by gene families showing a remarkable genetic diversity. Thus, NKR haplotypes contain several genes encoding for receptors with activating and inhibiting signaling, and that vary in gene content and allelic polymorphism. But if missing-self detection can be achieved by a monomorphic NKR system why have these polygenic and polymorphic receptors evolved? Here, we review the expansion of NKR receptor families in different mammal species, and we discuss several hypotheses that possibly underlie the diversification of the NK cell receptor complex, including the evolution of viral decoys, peptide sensitivity, and selective MHC-downregulation.
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Ansari AW, Ahmad F, Meyer-Olson D, Kamarulzaman A, Jacobs R, Schmidt RE. Natural killer cell heterogeneity: cellular dysfunction and significance in HIV-1 immuno-pathogenesis. Cell Mol Life Sci 2015; 72:3037-49. [PMID: 25939268 PMCID: PMC11113101 DOI: 10.1007/s00018-015-1911-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2015] [Revised: 04/17/2015] [Accepted: 04/20/2015] [Indexed: 11/28/2022]
Abstract
Natural killer (NK) cells are innate immune effectors that provide first line of defence against viruses. Human NK cells are heterogeneous in nature, and their functions rely on a dynamic balance between germ-line-encoded activating and inhibitory receptors. HIV-1 infection results in altered NK cell receptor repertoire and impaired effector functions including the ability to lyse virus-infected cells and secretion of antiviral cytokine IFN-γ. Over the last decade, additional NK cell subset-specific molecules have been identified, leading to emergence of a more complex cellular diversity than previously thought. Herein, we discuss NK cell subset redistribution, altered receptor repertoire and influence of interaction of polymorphic leucocyte antigen (HLA) and killer cell immunoglobulin-like receptors (KIR) on HIV-1 disease progression.
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Affiliation(s)
- A. Wahid Ansari
- Department of Clinical Immunology and Rheumatology, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany
- Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Lambah Pantai, 50603 Kuala Lumpur, Malaysia
- Department of Medicine, Faculty of Medicine, University of Malaya, Lambah Pantai, 50603 Kuala Lumpur, Malaysia
| | - Fareed Ahmad
- Department of Clinical Immunology and Rheumatology, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany
| | - Dirk Meyer-Olson
- Department of Clinical Immunology and Rheumatology, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany
| | - Adeeba Kamarulzaman
- Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Lambah Pantai, 50603 Kuala Lumpur, Malaysia
- Department of Medicine, Faculty of Medicine, University of Malaya, Lambah Pantai, 50603 Kuala Lumpur, Malaysia
| | - Roland Jacobs
- Department of Clinical Immunology and Rheumatology, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany
| | - Reinhold E. Schmidt
- Department of Clinical Immunology and Rheumatology, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany
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Impact of "Killer Immunoglobulin-Like Receptor /Ligand" Genotypes on Outcome following Surgery among Patients with Colorectal Cancer: Activating KIRs Are Associated with Long-Term Disease Free Survival. PLoS One 2015; 10:e0132526. [PMID: 26181663 PMCID: PMC4504472 DOI: 10.1371/journal.pone.0132526] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Accepted: 06/15/2015] [Indexed: 12/05/2022] Open
Abstract
Approximately 30 % of patients with stage II/III colorectal cancer develop recurrence following surgery. How individual regulation of host mediated anti-tumor cytotoxicity is modified by the killer-cell immunoglobulin-like receptor (KIRs) genotype is essential for prediction of outcome. We analyzed the frequency of KIR and KIR ligand Human Leukocyte Antigen Class I genotypes, and their effects on recurrence and disease-free survival (DFS). Out of randomly selected 87 colorectal cancer patients who underwent R0 resection operations between 2005 and 2008, 29 patients whose cancers progressed within a median five-year follow-up period were compared with 58 patients with no recurrence within the same time period. Recurrent cases shared similar tumor stages with non-recurrent cases, but had different localizations. We used DNA isolated from pathological archival lymphoid and tumor tissues for KIR and KIR ligand (HLA-C, group C1, group C2, and HLA-A-Bw4) genotyping. Among cases with recurrence, KIR2DL1 (inhibitory KIR) and A-Bw4 (ligand for inhibitory KIR3DL1) were observed more frequently (p=0.017 and p=0.024); and KIR2DS2 and KIR2DS3 (both activating KIRs) were observed less frequently (p=0.005 and p=0.043). Similarly, in the non-recurrent group, inhibitory KIR-ligand combinations 2DL1-C2 and 2DL3-C1 were less frequent, while the activating combination 2DS2-C1 was more frequent. The lack of KIR2DL1, 2DL1-C2, and 2DL3-C1 improved disease-free survival (DFS) (100% vs. 62.3%, p=0.05; 93.8% vs. 60.0%, p=0.035; 73.6% vs. 55.9%, p=0.07). The presence of KIR2DS2, 2DS3, and 2DS2-C1 improved DFS (77.8% vs. 48.5%, p=0.01; 79.4% vs. 58.5%, p=0.003; 76.9% vs. 51.4%, p=0.023). KIR2DS3 reduced the risk of recurrence (HR=0.263, 95% CI = 0.080-0.863, p=0.028). The number of activating KIRs are correlated strongly with DFS, none/ one/ two KIR : 54/77/98 months (p=0.004). In conclusion the inheritance of increasing numbers of activating KIRs and lack of inhibitory KIRs, independent of tumor localization or stage, is associated with long-term DFS.
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Carrillo-Bustamante P, Keşmir C, de Boer RJ. A Coevolutionary Arms Race between Hosts and Viruses Drives Polymorphism and Polygenicity of NK Cell Receptors. Mol Biol Evol 2015; 32:2149-60. [PMID: 25911231 PMCID: PMC4833080 DOI: 10.1093/molbev/msv096] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Natural killer cell receptors (NKRs) monitor the expression of major histocompatibility class I (MHC-I) and stress molecules to detect unhealthy tissue, such as infected or tumor cells. The NKR gene family shows a remarkable genetic diversity, containing several genes encoding receptors with activating and inhibiting signaling, and varying in gene content and allelic polymorphism. The expansion of the NKR genes is species-specific, with different species evolving alternative expanded NKR genes, which encode structurally different proteins, yet perform comparable functions. So far, the biological function of this expansion within the NKR cluster has remained poorly understood. To study the evolution of NKRs, we have developed an agent-based model implementing a coevolutionary scenario between hosts and herpes-like viruses that are able to evade the immune response by downregulating the expression of MHC-I on the cell surface. We show that hosts evolve specific inhibitory NKRs, specialized to particular MHC-I alleles in the population. Viruses in our simulations readily evolve proteins mimicking the MHC molecules of their host, even in the absence of MHC-I downregulation. As a result, the NKR locus becomes polygenic and polymorphic, encoding both specific inhibiting and activating receptors to optimally protect the hosts from coevolving viruses.
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Affiliation(s)
- Paola Carrillo-Bustamante
- Theoretical Biology & Bioinformatics, Department of Biology, Utrecht University, Utrecht, The Netherlands
| | - Can Keşmir
- Theoretical Biology & Bioinformatics, Department of Biology, Utrecht University, Utrecht, The Netherlands
| | - Rob J de Boer
- Theoretical Biology & Bioinformatics, Department of Biology, Utrecht University, Utrecht, The Netherlands
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Buchanan R, Hydes T, Khakoo SI. Innate and adaptive genetic pathways in HCV infection. TISSUE ANTIGENS 2015; 85:231-40. [PMID: 25708172 DOI: 10.1111/tan.12540] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Infection with hepatitis C virus (HCV) leads to a wide spectrum of clinical manifestations. This heterogeneity is underpinned by the host immune response and the genetic factors that govern it. Polymorphisms affecting both the innate and adaptive immunity determine the outcome of exposure. However the innate immune system appears to play a greater role in determining treatment-associated responses. Overall the effects of IFNL3/4 appear dominant over other polymorphic genes. Understanding how host genetics determines the disease phenotype has not been as intensively studied. This review summarizes our current understanding of innate and adaptive immunogenetic factors in the outcome of HCV infection. It focuses on how they relate to resolution and the progression of HCV-related liver disease, in the context of current and future treatment regimes.
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Affiliation(s)
- R Buchanan
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
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De Re V, Caggiari L, De Zorzi M, Repetto O, Zignego AL, Izzo F, Tornesello ML, Buonaguro FM, Mangia A, Sansonno D, Racanelli V, De Vita S, Pioltelli P, Vaccher E, Beretta M, Mazzaro C, Libra M, Gini A, Zucchetto A, Cannizzaro R, De Paoli P. Genetic diversity of the KIR/HLA system and susceptibility to hepatitis C virus-related diseases. PLoS One 2015; 10:e0117420. [PMID: 25700262 PMCID: PMC4336327 DOI: 10.1371/journal.pone.0117420] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 12/21/2014] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND The variability in the association of host innate immune response to Hepatitis C virus (HCV) infection requires ruling out the possible role of host KIR and HLA genotypes in HCV-related disorders: therefore, we therefore explored the relationships between KIR/HLA genotypes and chronic HCV infection (CHC) as they relate to the risk of HCV-related hepatocarcinoma (HCC) or lymphoproliferative disease progression. METHODS AND FINDINGS We analyzed data from 396 HCV-positive patients with CHC (n = 125), HCC (118), and lymphoproliferative diseases (153), and 501 HCV-negative patients. All were HIV and HBV negative. KIR-SSO was used to determine the KIR typing. KIR2DL5 and KIR2DS4 variants were performed using PCR and GeneScan analysis. HLA/class-I genotyping was performed using PCR-sequence-based typing. The interaction between the KIR gene and ligand HLA molecules was investigated. Differences in frequencies were estimated using Fisher's exact test, and Cochran-Armitage trend test. The non-random association of KIR alleles was estimated using the linkage disequilibrium test. We found an association of KIR2DS2/KIR2DL2 genes, with the HCV-related lymphoproliferative disorders. Furthermore, individuals with a HLA-Bw6 KIR3DL1+ combination of genes showed higher risk of developing lymphoma than cryoglobulinemia. KIR2DS3 gene was found to be the principal gene associated with chronic HCV infection, while a reduction of HLA-Bw4 + KIR3DS1+ was associated with an increased risk of developing HCC. CONCLUSIONS Our data highlight a role of the innate-system in developing HCV-related disorders and specifically KIR2DS3 and KIR2D genes demonstrated an ability to direct HCV disease progression, and mainly towards lymphoproliferative disorders. Moreover the determination of KIR3D/HLA combination of genes direct the HCV progression towards a lymphoma rather than an hepatic disease. In this contest IFN-α therapy, a standard therapy for HCV-infection and lymphoproliferative diseases, known to be able to transiently enhance the cytotoxicity of NK-cells support the role of NK cells to counterstain HCV-related and lymphoproliferative diseases.
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Affiliation(s)
- Valli De Re
- Facility Bio-proteomica/Dir. Sc, CRO National Cancer Institute, Aviano, Pordenone, Italy
| | - Laura Caggiari
- Facility Bio-proteomica/Dir. Sc, CRO National Cancer Institute, Aviano, Pordenone, Italy
| | - Mariangela De Zorzi
- Facility Bio-proteomica/Dir. Sc, CRO National Cancer Institute, Aviano, Pordenone, Italy
| | - Ombretta Repetto
- Facility Bio-proteomica/Dir. Sc, CRO National Cancer Institute, Aviano, Pordenone, Italy
| | - Anna Linda Zignego
- Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Francesco Izzo
- Hepatobiliary Unit, National Cancer Institute “Fondazione Pascale”, Naples, Italy
| | - Maria Lina Tornesello
- Molecular Biology and Viral Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy
| | - Franco Maria Buonaguro
- Molecular Biology and Viral Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy
| | - Alessandra Mangia
- Liver, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
| | - Domenico Sansonno
- Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Vito Racanelli
- Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Salvatore De Vita
- Medical and Biological Sciences, University Hospital Santa Maria della Misericordia, Udine, Italy
| | - Pietro Pioltelli
- Hematology and Transplant Unit, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
| | - Emanuela Vaccher
- Medical Oncology, Centro di riferimento oncologico, Aviano, Pordenone, Italy
| | | | - Cesare Mazzaro
- Medical Oncology, Centro di riferimento oncologico, Aviano, Pordenone, Italy
| | - Massimo Libra
- Biomedical Sciences, University of Catania, Catania, Italy
| | - Andrea Gini
- Epidemiology and Biostatistics, CRO National Cancer Institute, Aviano, Pordenone, Italy
| | - Antonella Zucchetto
- Epidemiology and Biostatistics, CRO National Cancer Institute, Aviano, Pordenone, Italy
| | - Renato Cannizzaro
- Gastroenterology, CRO National Cancer Institute, Aviano, Pordenone, Italy
| | - Paolo De Paoli
- Facility Bio-proteomica/Dir. Sc, CRO National Cancer Institute, Aviano, Pordenone, Italy
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Kim HJ, Choi HB, Jang JP, Baek IC, Choi EJ, Park M, Kim TG, Oh ST. HLA-Cw polypmorphism and killer cell immunoglobulin-like receptor (KIR) gene analysis in Korean colorectal cancer patients. Int J Surg 2014; 12:815-20. [PMID: 24998207 DOI: 10.1016/j.ijsu.2014.06.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 06/03/2014] [Accepted: 06/22/2014] [Indexed: 11/24/2022]
Abstract
PURPOSE Natural killer cells (NK cells) play important roles in protecting the patient from the early development of cancers, and are activated or inhibited by killer cell immunoglobulin-like receptors (KIR), which bind to HLA class I. In the present study, we investigated the KIR genotype of Korean colorectal cancer patients. METHODS DNA samples were extracted from peripheral blood cell samples taken from Korean colorectal cancer patients and a control group. KIR genes were amplified using PCR-SSP methods, and HLA-Cw genes were characterized using PCR methods. The results were analyzed to assess the difference between colorectal cancer patients and the normal control group. RESULTS In the present study, the frequency of KIR2DS5 (33.2% vs. 20.8%, p-value < 0.007) was higher in the colorectal cancer group, and in the rectal cancer subgroup, the frequencies of KIR3DL1 (93.2%, vs. 98.1%, p-value < 0.05), KIR2DS2 (7.8% vs. 19.5%, p-value < 0.01), and KIR2DS4 (93.2% vs. 98.1%, p-value < 0.05) were lower significantly. The frequencies of HLA-Cw6 (9.1% vs. 15.7%, p-value < 0.05) and HLA-Cw7 (17.4% vs. 27.7%, p-value < 0.02) were lower in the colorectal cancer group. Of the patients with HLA-C1 homozygote, the frequency of KIR2DS2 was decreased significantly (5.8% vs. 14.5%, p-value < 0.004). CONCLUSIONS The frequency of KIR2DS5 is higher in Korean colorectal cancer patients, and in the rectal cancer subgroup, the frequencies of KIR3DL1, KIR2DS2 and KIR2DS4 are lower. Among the patients with HLA-C1 homozygote, the frequency of KIR2DS2 is decreased. Therefore, KIR2DS2 in presence of its ligand (HLA-C1 group) may have a protective effect against colorectal cancer.
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Affiliation(s)
- Hyung-Jin Kim
- Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hae-Baeg Choi
- Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung-Pil Jang
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - In-Cheol Baek
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun-Jeong Choi
- Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Miyoung Park
- Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Tai-Gyu Kim
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
| | - Seong-Taek Oh
- Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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Natural killer cell function and dysfunction in hepatitis C virus infection. BIOMED RESEARCH INTERNATIONAL 2014; 2014:903764. [PMID: 25057504 PMCID: PMC4095668 DOI: 10.1155/2014/903764] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Accepted: 04/14/2014] [Indexed: 01/06/2023]
Abstract
Viruses must continually adapt against dynamic innate and adaptive responses of the host immune system to establish chronic infection. Only a small minority (~20%) of those exposed to hepatitis C virus (HCV) spontaneously clear infection, leaving approximately 200 million people worldwide chronically infected with HCV. A number of recent research studies suggest that establishment and maintenance of chronic HCV infection involve natural killer (NK) cell dysfunction. This relationship is illustrated in vitro by disruption of typical NK cell responses including both cell-mediated cytotoxicity and cytokine production. Expression of a number of activating NK cell receptors in vivo is also affected in chronic HCV infection. Thus, direct in vivo and in vitro evidence of compromised NK function in chronic HCV infection in conjunction with significant epidemiological associations between the outcome of HCV infection and certain combinations of NK cell regulatory receptor and class I human histocompatibility linked antigen (HLA) genotypes indicate that NK cells are important in the immune response against HCV infection. In this review, we highlight evidence suggesting that selective impairment of NK cell activity is related to establishment of chronic HCV infection.
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Vidal-Castiñeira JR, López-Vázquez A, Martínez-Borra J, Martínez-Camblor P, Prieto J, López-Rodríguez R, Sanz-Cameno P, de la Vega J, Rodrigo L, Pérez-López R, Pérez-Álvarez R, López-Larrea C. Diversity of killer cell immunoglobulin-like receptor (KIR) genotypes and KIR2DL2/3 variants in HCV treatment outcome. PLoS One 2014; 9:e99426. [PMID: 24927414 PMCID: PMC4057177 DOI: 10.1371/journal.pone.0099426] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Accepted: 05/14/2014] [Indexed: 01/22/2023] Open
Abstract
The aim of this study was to analyse the distribution of KIR haplotypes and the KIR2DL2/3 alleles in chronic HCV-infected patients in order to establish the influence on the response to pegylated interferon plus ribavirin classical treatment. The alleles study of previously associated KIR2DL2/3 showed that KIR2DL2*001 was more frequent in non-SVR (NSVR) (42.2% vs. 27.5%, p<0.05) and KIR2DL3*001 was associated with sustained viral response (SVR) (41.6% vs. 61.2%, p<0.005). The KIR2DL3*001-HLA-C1 association was also significant (24.5% vs. 45.7%, p<0.001). From the frequencies of KIR obtained, 35 genotypes were assigned on the basis of previous studies. The centromeric A/A genotype was more frequent in SVR (44.1% vs. 34.5%, p<0.005) and the centromeric B/B genotype was found to be significantly more frequent in NSVR (20.9% vs. 11.2%, p<0.001). The logic regression model showed the importance of KIR genes in predicting the response to combined treatment, since the positive predictive value (PPV) was improved (from 55.9% to 75.3%) when the analysis of KIR was included in addition to the IFNL3 rs12979860 polymorphism. The study of KIR receptors may be a powerful tool for predicting the combined treatment response in patients with chronic HCV infection in association with the determination of IFNL3 polymorphism.
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Affiliation(s)
| | | | | | | | - Jesús Prieto
- Liver Unit and Division of Hepatology and Gene Therapy, Clínica Universitaria de Navarra, University of Navarra, Pamplona, Spain
| | - Rosario López-Rodríguez
- Liver Unit, Gastroenterology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid and CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Paloma Sanz-Cameno
- Liver Unit, Gastroenterology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid and CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Juan de la Vega
- Gastroenterology Service, Hospital San Agustín, Avilés, Spain
| | - Luis Rodrigo
- Gastroenterology Service, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Rosa Pérez-López
- Gastroenterology Service, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Ramón Pérez-Álvarez
- Gastroenterology Service, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Carlos López-Larrea
- Immunology Service, Hospital Universitario Central de Asturias, Oviedo, Spain
- Fundación Renal Iñigo Álvarez de Toledo, Madrid, Spain
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Carrillo-Bustamante P, Keşmir C, de Boer RJ. Quantifying the Protection of Activating and Inhibiting NK Cell Receptors during Infection with a CMV-Like Virus. Front Immunol 2014; 5:20. [PMID: 24523722 PMCID: PMC3906586 DOI: 10.3389/fimmu.2014.00020] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 01/15/2014] [Indexed: 11/16/2022] Open
Abstract
The responsiveness of natural killer (NK) cells is controlled by balancing signals from activating and inhibitory receptors. The most important ligands of inhibitory NK cell receptors are the highly polymorphic major histocompatibility complex (MHC) class I molecules, which allow NK cells to screen the cellular health of target cells. Although these inhibitory receptor–ligand interactions have been well characterized, the ligands for most activating receptors are still unknown. The mouse cytomegalovirus (MCMV) represents a helpful model to study NK cell-driven immune responses. Many studies have demonstrated that CMV infection can be controlled by NK cells via their activating receptors, but the exact contribution of the different signaling potential (i.e., activating vs. inhibiting) remains puzzling. In this study, we have developed a probabilistic model, which predicts the optimal specificity of inhibitory and activating NK cell receptors needed to offer the best protection against a CMV-like virus. We confirm our analytical predictions with an agent-based model of an evolving host population. Our analysis quantifies the degree of protection of each receptor type, revealing that mixed haplotypes (i.e., haplotypes composed of activating and inhibiting receptors) are most protective against CMV-like viruses, and that the protective effect depends on the number of MHC loci per individual.
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Affiliation(s)
- Paola Carrillo-Bustamante
- Theoretical Biology and Bioinformatics, Department of Biology, Utrecht University , Utrecht , Netherlands
| | - Can Keşmir
- Theoretical Biology and Bioinformatics, Department of Biology, Utrecht University , Utrecht , Netherlands
| | - Rob J de Boer
- Theoretical Biology and Bioinformatics, Department of Biology, Utrecht University , Utrecht , Netherlands
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O'Connor GM, McVicar D. The yin-yang of KIR3DL1/S1: molecular mechanisms and cellular function. Crit Rev Immunol 2014; 33:203-18. [PMID: 23756244 DOI: 10.1615/critrevimmunol.2013007409] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Killer Immunoglobulin-like Receptors (KIR) are a family of receptors expressed on natural killer (NK) and T-cell subsets. KIR3DL1 is a highly polymorphic receptor that binds to groups of HLAA and HLA-B allotypes that express the Bw4 epitope. The variation in KIR3DL1 allotypes manifests at a number of levels. Most dramatically, a common allelic variant encodes an activating rather than an inhibitory receptor (KIR3DS1). In addition, sequence variants can affect both the frequency of expression within the NK cell population and the intensity of expression on a given cell. KIR3DL1 polymorphism also influences the interaction with HLA-Bw4 molecules, due to contacts with the HLA molecule itself and sensitivity to the presented peptide. A body of evidence from genetic association studies supports the biological significance not only of the interaction of KIR3DL1 with HLA-Bw4 but also the functional variation seen with different KIR3DL1 and HLA allotypes. In this review, we discuss our current understanding of KIR3DL1 function and our recent insights from the structure of the KIR3DL1 in complex with HLA. In addition, we will summarize our current understanding of KIR3DS1, including its ligand specificity and its role in immune responses.
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Affiliation(s)
- Geraldine M O'Connor
- Cancer and Inflammation Program, National Cancer Institute at Frederick, NIH, Frederick, MD 21702, USA
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Nozawa Y, Umemura T, Joshita S, Katsuyama Y, Shibata S, Kimura T, Morita S, Komatsu M, Matsumoto A, Tanaka E, Ota M. KIR, HLA, and IL28B variant predict response to antiviral therapy in genotype 1 chronic hepatitis C patients in Japan. PLoS One 2013; 8:e83381. [PMID: 24349500 PMCID: PMC3861489 DOI: 10.1371/journal.pone.0083381] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Accepted: 11/02/2013] [Indexed: 01/17/2023] Open
Abstract
Natural killer cell responses play a crucial role in virus clearance by the innate immune system. Although the killer immunoglobulin-like receptor (KIR) in combination with its cognate human leukocyte antigen (HLA) ligand, especially KIR2DL3-HLA-C1, is associated with both treatment-induced and spontaneous clearance of hepatitis C virus (HCV) infection in Caucasians, these innate immunity genes have not been fully clarified in Japanese patients. We therefore investigated 16 KIR genotypes along with HLA-B and -C ligands and a genetic variant of interleukin (IL) 28B (rs8099917) in 115 chronic hepatitis C genotype 1 patients who underwent pegylated-interferon-α2b (PEG-IFN) and ribavirin therapy. HLA-Bw4 was significantly associated with a sustained virological response (SVR) to treatment (P = 0.017; odds ratio [OR] = 2.50, ), as was the centromeric A/A haplotype of KIR (P = 0.015; OR 3.37). In contrast, SVR rates were significantly decreased in patients with KIR2DL2 or KIR2DS2 (P = 0.015; OR = 0.30, and P = 0.025; OR = 0.32, respectively). Multivariate logistic regression analysis subsequently identified the IL28B TT genotype (P = 0.00009; OR = 6.87, 95% confidence interval [CI] = 2.62 - 18.01), KIR2DL2/HLA-C1 (P = 0.014; OR = 0.24, 95% CI = 0.08 - 0.75), KIR3DL1/HLA-Bw4 (P = 0.008, OR = 3.32, 95% CI = 1.37 - 8.05), and white blood cell count at baseline (P = 0.009; OR = 3.32, 95% CI = 1.35 - 8.16) as independent predictive factors of an SVR. We observed a significant association between the combination of IL28B TT genotype and KIR3DL1-HLA-Bw4 in responders (P = 0.0019), whereas IL28B TT along with KIR2DL2-HLA-C1 was related to a non-response (P = 0.0067). In conclusion, combinations of KIR3DL1/HLA-Bw4, KIR2DL2/HLA-C1, and a genetic variant of the IL28B gene are predictive of the response to PEG-IFN and ribavirin therapy in Japanese patients infected with genotype 1b HCV.
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Affiliation(s)
- Yuichi Nozawa
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeji Umemura
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Joshita
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | | | - Soichiro Shibata
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takefumi Kimura
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Susumu Morita
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Michiharu Komatsu
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akihiro Matsumoto
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Eiji Tanaka
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Masao Ota
- Department of Legal Medicine, Shinshu University School of Medicine, Matsumoto, Japan
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Ahlenstiel G. The natural killer cell response to HCV infection. Immune Netw 2013; 13:168-76. [PMID: 24198741 PMCID: PMC3817297 DOI: 10.4110/in.2013.13.5.168] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Revised: 08/29/2013] [Accepted: 09/03/2013] [Indexed: 02/07/2023] Open
Abstract
In the last few years major progress has been made in better understanding the role of natural killer (NK) cells in hepatitis C virus (HCV) infection. This includes multiple pathways by which HCV impairs or limits NK cells activation. Based on current genetic and functional data, a picture is emerging where only a rapid and strong NK cell response early on during infection which results in strong T cell responses and possible subsequent clearance, whereas chronic HCV infection is associated with dysfunctional or biased NK cells phenotypes. The hallmark of this NK cell dysfunction is persistent activation promoting ongoing hepatitis and hepatocyte damage, while being unable to clear HCV due to impaired IFN-γ responses. Furthermore, some data suggests certain chronically activated subsets that are NKp46high may be particularly active against hepatic stellate cells, a key player in hepatic fibrogenesis. Finally, the role of NK cells during HCV therapy, HCV recurrence after liver transplant and hepatocellular carcinoma are discussed.
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Affiliation(s)
- Golo Ahlenstiel
- Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, Australia
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49
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Cariani E, Pilli M, Zerbini A, Rota C, Olivani A, Zanelli P, Zanetti A, Trenti T, Ferrari C, Missale G. HLA and killer immunoglobulin-like receptor genes as outcome predictors of hepatitis C virus-related hepatocellular carcinoma. Clin Cancer Res 2013; 19:5465-73. [PMID: 23938290 DOI: 10.1158/1078-0432.ccr-13-0986] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE We evaluated the impact of the killer immunoglobulin-like receptors (KIR) of natural killer (NK) cells and of their HLA ligands over the clinical outcome of hepatitis C virus (HCV)-related hepatocellular carcinoma after curative treatment by either surgical resection or radiofrequency thermal ablation (RTA). EXPERIMENTAL DESIGN Sixty-one consecutive patients with HCV-related hepatocellular carcinoma underwent KIR genotyping and HLA typing. A phenotypic/functional characterization of NK cells was carried out in patients with different KIR/KIR-ligand genotype. RESULTS Activating KIR2DS5 was associated with significantly longer time to recurrence (TTR) and overall survival (OS; P < 0.03 each). Homozygous HLA-C1 (P < 0.02) and HLA-Bw4I80 (P < 0.05) were expressed by patients with significantly better OS, whereas HLA-C2 (P < 0.02) and HLA-Bw4T80 (P < 0.01) were associated with a worse OS. Multivariate analysis identified as parameters independently related to TTR the type of treatment (surgical resection vs. RTA; P < 0.03) and HLA-C1 (P < 0.03), whereas only KIR2DS5 was an independent predictor of longer OS (P < 0.05). Compound KIR2DL2-C1 and KIR3DS1-Bw4T80 genotypes were associated with better TTR (P < 0.03) and worse OS (P = 0.02), respectively. A prevalent cytotoxic (CD56(dim)) NK phenotype was detected in patients with both longer TTR and OS. Cytotoxic capacity measured by upregulation of CD107a was significantly higher in subjects with HLA-C1 alone or combined with KIR2DL2/KIR2DL3. CONCLUSIONS These results support a central role of NK cells in the immune response against hepatocellular carcinoma, providing a strong rationale for therapeutic strategies enhancing NK response and for individualized posttreatment monitoring schemes.
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Affiliation(s)
- Elisabetta Cariani
- Authors' Affiliations: Clinical Pathology-Toxicology, Ospedale S. Agostino-Estense, Modena; U.O. Infectious Diseases and Hepatology; U.O. Medical Genetics, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; and Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Department of Laboratory Medicine, Azienda Ospedaliera ASMN, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy
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50
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Natural killer cell response to BK virus infection in polyoma virus–associated nephropathy of renal transplant recipients. Kidney Int 2013; 84:233-5. [DOI: 10.1038/ki.2013.148] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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