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1
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Joyce S, Okoye GD, Driver JP. Die Kämpfe únd schláchten-the struggles and battles of innate-like effector T lymphocytes with microbes. Front Immunol 2023; 14:1117825. [PMID: 37168859 PMCID: PMC10165076 DOI: 10.3389/fimmu.2023.1117825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 03/22/2023] [Indexed: 05/13/2023] Open
Abstract
The large majority of lymphocytes belong to the adaptive immune system, which are made up of B2 B cells and the αβ T cells; these are the effectors in an adaptive immune response. A multitudinous group of lymphoid lineage cells does not fit the conventional lymphocyte paradigm; it is the unconventional lymphocytes. Unconventional lymphocytes-here called innate/innate-like lymphocytes, include those that express rearranged antigen receptor genes and those that do not. Even though the innate/innate-like lymphocytes express rearranged, adaptive antigen-specific receptors, they behave like innate immune cells, which allows them to integrate sensory signals from the innate immune system and relay that umwelt to downstream innate and adaptive effector responses. Here, we review natural killer T cells and mucosal-associated invariant T cells-two prototypic innate-like T lymphocytes, which sense their local environment and relay that umwelt to downstream innate and adaptive effector cells to actuate an appropriate host response that confers immunity to infectious agents.
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Affiliation(s)
- Sebastian Joyce
- Department of Veterans Affairs, Tennessee Valley Healthcare Service, Nashville, TN, United States
- Department of Pathology, Microbiology and Immunology, The Vanderbilt Institute for Infection, Immunology and Inflammation and Vanderbilt Center for Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Gosife Donald Okoye
- Department of Pathology, Microbiology and Immunology, The Vanderbilt Institute for Infection, Immunology and Inflammation and Vanderbilt Center for Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - John P. Driver
- Division of Animal Sciences, University of Missouri, Columbia, MO, United States
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2
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Khan MA, Khan A. Role of NKT Cells during Viral Infection and the Development of NKT Cell-Based Nanovaccines. Vaccines (Basel) 2021; 9:vaccines9090949. [PMID: 34579186 PMCID: PMC8473043 DOI: 10.3390/vaccines9090949] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 08/16/2021] [Accepted: 08/23/2021] [Indexed: 12/30/2022] Open
Abstract
Natural killer T (NKT) cells, a small population of T cells, are capable of influencing a wide range of the immune cells, including T cells, B cells, dendritic cells and macrophages. In the present review, the antiviral role of the NKT cells and the strategies of viruses to evade the functioning of NKT cell have been illustrated. The nanoparticle-based formulations have superior immunoadjuvant potential by facilitating the efficient antigen processing and presentation that favorably elicits the antigen-specific immune response. Finally, the immunoadjuvant potential of the NKT cell ligand was explored in the development of antiviral vaccines. The use of an NKT cell-activating nanoparticle-based vaccine delivery system was supported in order to avoid the NKT cell anergy. The results from the animal and preclinical studies demonstrated that nanoparticle-incorporated NKT cell ligands may have potential implications as an immunoadjuvant in the formulation of an effective antiviral vaccine that is capable of eliciting the antigen-specific activation of the cell-mediated and humoral immune responses.
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3
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Liu J, Yang X, Wang H, Li Z, Deng H, Liu J, Xiong S, He J, Feng X, Guo C, Wang W, Zelinskyy G, Trilling M, Sutter K, Senff T, Menne C, Timm J, Zhang Y, Deng F, Lu Y, Wu J, Lu M, Yang D, Dittmer U, Wang B, Zheng X. Analysis of the Long-Term Impact on Cellular Immunity in COVID-19-Recovered Individuals Reveals a Profound NKT Cell Impairment. mBio 2021; 12:e00085-21. [PMID: 33906918 PMCID: PMC8092197 DOI: 10.1128/mbio.00085-21] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 03/30/2021] [Indexed: 01/13/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affected over 120 million people and killed over 2.7 million individuals by March 2021. While acute and intermediate interactions between SARS-CoV-2 and the immune system have been studied extensively, long-term impacts on the cellular immune system remain to be analyzed. Here, we comprehensively characterized immunological changes in peripheral blood mononuclear cells in 49 COVID-19-convalescent individuals (CI) in comparison to 27 matched SARS-CoV-2-unexposed individuals (UI). Despite recovery from the disease for more than 2 months, CI showed significant decreases in frequencies of invariant NKT and NKT-like cells compared to UI. Concomitant with the decrease in NKT-like cells, an increase in the percentage of annexin V and 7-aminoactinomycin D (7-AAD) double-positive NKT-like cells was detected, suggesting that the reduction in NKT-like cells results from cell death months after recovery. Significant increases in regulatory T cell frequencies and TIM-3 expression on CD4 and CD8 T cells were also observed in CI, while the cytotoxic potential of T cells and NKT-like cells, defined by granzyme B (GzmB) expression, was significantly diminished. However, both CD4 and CD8 T cells of CI showed increased Ki67 expression and were fully able to proliferate and produce effector cytokines upon T cell receptor (TCR) stimulation. Collectively, we provide a comprehensive characterization of immune signatures in patients recovering from SARS-CoV-2 infection, suggesting that the cellular immune system of COVID-19 patients is still under a sustained influence even months after the recovery from disease.IMPORTANCE Wuhan was the very first city hit by SARS-CoV-2. Accordingly, the patients who experienced the longest phase of convalescence following COVID-19 reside here. This enabled us to investigate the "immunological scar" left by SARS-CoV-2 on cellular immunity after recovery from the disease. In this study, we characterized the long-term impact of SARS-CoV-2 infection on the immune system and provide a comprehensive picture of cellular immunity of a convalescent COVID-19 patient cohort with the longest recovery time. We revealed that the cellular immune system of COVID-19 patients is still under a sustained influence even months after the recovery from disease; in particular, a profound NKT cell impairment was found in the convalescent phase of COVID-19.
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Affiliation(s)
- Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Xuecheng Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Hua Wang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ziwei Li
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Deng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Shue Xiong
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Junyi He
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Xuemei Feng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Chunxia Guo
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weixian Wang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gennadiy Zelinskyy
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Mirko Trilling
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Kathrin Sutter
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Tina Senff
- Institute for Virology, Heinrich-Heine-University, University Hospital, Duesseldorf, Germany
| | - Christopher Menne
- Institute for Virology, Heinrich-Heine-University, University Hospital, Duesseldorf, Germany
| | - Joerg Timm
- Institute for Virology, Heinrich-Heine-University, University Hospital, Duesseldorf, Germany
| | - Yanfang Zhang
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Fei Deng
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Yinping Lu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Wu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Mengji Lu
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Ulf Dittmer
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Baoju Wang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Zheng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
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4
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Gálvez NMS, Bohmwald K, Pacheco GA, Andrade CA, Carreño LJ, Kalergis AM. Type I Natural Killer T Cells as Key Regulators of the Immune Response to Infectious Diseases. Clin Microbiol Rev 2021; 34:e00232-20. [PMID: 33361143 PMCID: PMC7950362 DOI: 10.1128/cmr.00232-20] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The immune system must work in an orchestrated way to achieve an optimal response upon detection of antigens. The cells comprising the immune response are traditionally divided into two major subsets, innate and adaptive, with particular characteristics for each type. Type I natural killer T (iNKT) cells are defined as innate-like T cells sharing features with both traditional adaptive and innate cells, such as the expression of an invariant T cell receptor (TCR) and several NK receptors. The invariant TCR in iNKT cells interacts with CD1d, a major histocompatibility complex class I (MHC-I)-like molecule. CD1d can bind and present antigens of lipid nature and induce the activation of iNKT cells, leading to the secretion of various cytokines, such as gamma interferon (IFN-γ) and interleukin 4 (IL-4). These cytokines will aid in the activation of other immune cells following stimulation of iNKT cells. Several molecules with the capacity to bind to CD1d have been discovered, including α-galactosylceramide. Likewise, several molecules have been synthesized that are capable of polarizing iNKT cells into different profiles, either pro- or anti-inflammatory. This versatility allows NKT cells to either aid or impair the clearance of pathogens or to even control or increase the symptoms associated with pathogenic infections. Such diverse contributions of NKT cells to infectious diseases are supported by several publications showing either a beneficial or detrimental role of these cells during diseases. In this article, we discuss current data relative to iNKT cells and their features, with an emphasis on their driving role in diseases produced by pathogenic agents in an organ-oriented fashion.
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Affiliation(s)
- Nicolás M S Gálvez
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Karen Bohmwald
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gaspar A Pacheco
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Catalina A Andrade
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Leandro J Carreño
- Millennium Institute on Immunology and Immunotherapy, Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Alexis M Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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5
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Hashemi E, Malarkannan S. Tissue-Resident NK Cells: Development, Maturation, and Clinical Relevance. Cancers (Basel) 2020; 12:cancers12061553. [PMID: 32545516 PMCID: PMC7352973 DOI: 10.3390/cancers12061553] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/08/2020] [Accepted: 06/08/2020] [Indexed: 12/14/2022] Open
Abstract
Natural killer (NK) cells belong to type 1 innate lymphoid cells (ILC1) and are essential in killing infected or transformed cells. NK cells mediate their effector functions using non-clonotypic germ-line-encoded activation receptors. The utilization of non-polymorphic and conserved activating receptors promoted the conceptual dogma that NK cells are homogeneous with limited but focused immune functions. However, emerging studies reveal that NK cells are highly heterogeneous with divergent immune functions. A distinct combination of several activation and inhibitory receptors form a diverse array of NK cell subsets in both humans and mice. Importantly, one of the central factors that determine NK cell heterogeneity and their divergent functions is their tissue residency. Decades of studies provided strong support that NK cells develop in the bone marrow. However, evolving evidence supports the notion that NK cells also develop and differentiate in tissues. Here, we summarize the molecular basis, phenotypic signatures, and functions of tissue-resident NK cells and compare them with conventional NK cells.
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Affiliation(s)
- Elaheh Hashemi
- Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI 53226, USA;
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Subramaniam Malarkannan
- Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI 53226, USA;
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Correspondence:
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6
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Chen Y, Yu M, Zheng Y, Fu G, Xin G, Zhu W, Luo L, Burns R, Li QZ, Dent AL, Zhu N, Cui W, Malherbe L, Wen R, Wang D. CXCR5 +PD-1 + follicular helper CD8 T cells control B cell tolerance. Nat Commun 2019; 10:4415. [PMID: 31562329 PMCID: PMC6765049 DOI: 10.1038/s41467-019-12446-5] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 09/04/2019] [Indexed: 01/31/2023] Open
Abstract
Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance. B cell response and antibody production are generally facilitated by CD4+ follicular helper (Tfh) cells. Here the authors identify a subset of CXCR5+PD1+CD8+ Tfh cells that is normally suppressed by STAT5 signaling, so that STAT5 deficiency in mice increases the number of these CD8+ Tfh cells and induces concomitant production of autoantibodies.
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Affiliation(s)
- Yuhong Chen
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Mei Yu
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Yongwei Zheng
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Guoping Fu
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Gang Xin
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Wen Zhu
- Blood Research Institute, Versiti, Milwaukee, WI, USA.,Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Lan Luo
- Blood Research Institute, Versiti, Milwaukee, WI, USA.,Chinese PLA General Hospital, Beijing, China
| | - Robert Burns
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Quan-Zhen Li
- Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Alexander L Dent
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Nan Zhu
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Weiguo Cui
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | | | - Renren Wen
- Blood Research Institute, Versiti, Milwaukee, WI, USA
| | - Demin Wang
- Blood Research Institute, Versiti, Milwaukee, WI, USA. .,Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA. .,Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian, China.
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7
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Liu J, Gallo RM, Khan MA, Iyer AK, Kratzke IM, Brutkiewicz RR. JNK2 modulates the CD1d-dependent and -independent activation of iNKT cells. Eur J Immunol 2018; 49:255-265. [PMID: 30467836 DOI: 10.1002/eji.201847755] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 10/30/2018] [Accepted: 11/21/2018] [Indexed: 01/01/2023]
Abstract
Invariant natural killer T (iNKT) cells play critical roles in autoimmune, anti-tumor, and anti-microbial immune responses, and are activated by glycolipids presented by the MHC class I-like molecule, CD1d. How the activation of signaling pathways impacts antigen (Ag)-dependent iNKT cell activation is not well-known. In the current study, we found that the MAPK JNK2 not only negatively regulates CD1d-mediated Ag presentation in APCs, but also contributes to CD1d-independent iNKT cell activation. A deficiency in the JNK2 (but not JNK1) isoform enhanced Ag presentation by CD1d. Using a vaccinia virus (VV) infection model known to cause a loss in iNKT cells in a CD1d-independent, but IL-12-dependent manner, we found the virus-induced loss of iNKT cells in JNK2 KO mice was substantially lower than that observed in JNK1 KO or wild-type (WT) mice. Importantly, compared to WT mice, JNK2 KO mouse iNKT cells were found to express less surface IL-12 receptors. As with a VV infection, an IL-12 injection also resulted in a smaller decrease in JNK2 KO iNKT cells as compared to WT mice. Overall, our work strongly suggests JNK2 is a negative regulator of CD1d-mediated Ag presentation and contributes to IL-12-induced iNKT cell activation and loss during viral infections.
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Affiliation(s)
- Jianyun Liu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Richard M Gallo
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Masood A Khan
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.,College of Applied Medical Sciences, Al-Qassim University, Buraidah, Saudi Arabia
| | - Abhirami K Iyer
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Ian M Kratzke
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Randy R Brutkiewicz
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
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8
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Rao P, Wen X, Lo JH, Kim S, Li X, Chen S, Feng X, Akbari O, Yuan W. Herpes Simplex Virus 1 Specifically Targets Human CD1d Antigen Presentation To Enhance Its Pathogenicity. J Virol 2018; 92:e01490-18. [PMID: 30185591 PMCID: PMC6206489 DOI: 10.1128/jvi.01490-18] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 08/29/2018] [Indexed: 12/19/2022] Open
Abstract
Herpes simplex virus 1 (HSV-1) is one of the most prevalent herpesviruses in humans and represents a constant health threat to aged and immunocompromised populations. How HSV-1 interacts with the host immune system to efficiently establish infection and latency is only partially known. CD1d-restricted NKT cells are a critical arm of the host innate immune system and play potent roles in anti-infection and antitumor immune responses. We discovered previously that upon infection, HSV-1 rapidly and efficiently downregulates CD1d expression on the cell surface and suppresses the function of NKT cells. Furthermore, we identified the viral serine/threonine protein kinase US3 as a major viral factor downregulating CD1d during infection. Interestingly, neither HSV-1 nor its US3 protein efficiently inhibits mouse CD1d expression, suggesting that HSV-1 has coevolved with the human immune system to specifically suppress human CD1d (hCD1d) and NKT cell function for its pathogenesis. This is consistent with the fact that wild-type mice are mostly resistant to HSV-1 infection. On the other hand, in vivo infection of CD1d-humanized mice (hCD1d knock-in mice) showed that HSV-1 can indeed evade hCD1d function and establish infection in these mice. We also report here that US3-deficient viruses cannot efficiently infect hCD1d knock-in mice but infect mice lacking all NKT cells at a higher efficiency. Together, these studies supported HSV-1 evasion of human CD1d and NKT cell function as an important pathogenic factor for the virus. Our results also validated the potent roles of NKT cells in antiherpesvirus immune responses and pointed to the potential of NKT cell ligands as adjuvants for future vaccine development.IMPORTANCE Herpes simplex virus 1 (HSV-1) is among the most common human pathogens. Little is known regarding the exact mechanism by which this virus evades the human immune system, particularly the innate immune system. We reported previously that HSV-1 employs its protein kinase US3 to modulate the expression of the key antigen-presenting molecule, CD1d, so as to evade the antiviral function of NKT cells. Here we demonstrated that the virus has coevolved with the human CD1d and NKT cell system and that NKT cells indeed play potent roles in anti-HSV immune responses. These studies point to the great potential of exploring NKT cell ligands as adjuvants for HSV vaccines.
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Affiliation(s)
- Ping Rao
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Xiangshu Wen
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Jae Ho Lo
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Seil Kim
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Xin Li
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Siyang Chen
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Xiaotian Feng
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Omid Akbari
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Weiming Yuan
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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9
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Brutkiewicz RR, Yunes-Medina L, Liu J. Immune evasion of the CD1d/NKT cell axis. Curr Opin Immunol 2018; 52:87-92. [PMID: 29734045 DOI: 10.1016/j.coi.2018.04.021] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 04/19/2018] [Indexed: 01/03/2023]
Abstract
Many reviews on the CD1d/NKT cell axis focus on the ability of CD1d-restricted NKT cells to serve as effector cells in a variety of disorders, be they infectious diseases, cancer or autoimmunity. In contrast, here, we discuss the ways that viruses, bacteria and tumor cells can evade the CD1d/NKT cell axis. As a result, these disease states have a better chance to establish a foothold and potentially cause problems for the subsequent adaptive immune response, as the host tries to rid itself of infections or tumors.
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Affiliation(s)
- Randy R Brutkiewicz
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202-5181, United States.
| | - Laura Yunes-Medina
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202-5181, United States
| | - Jianyun Liu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202-5181, United States
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10
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Tan AHM, Sanny A, Ng SW, Ho YS, Basri N, Lee AP, Lam KP. Excessive interferon-α signaling in autoimmunity alters glycosphingolipid processing in B cells. J Autoimmun 2017; 89:53-62. [PMID: 29191573 DOI: 10.1016/j.jaut.2017.11.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 11/14/2017] [Accepted: 11/16/2017] [Indexed: 01/01/2023]
Abstract
Excessive interferon-α (IFN-α) production by innate immune cells is a hallmark of autoimmune diseases. What other cell type secretes IFN-α and how IFN-α affects immune cell metabolism and homeostasis in autoimmunity are largely unclear. Here, we report that autoimmune B cells, arising from two different B cell-specific genetic lesions in mice, secrete IFN-α. In addition, IFN-α, found in abundance in autoimmunity, elicited profound changes in the B cell lipidome, increasing their expression of glycosphingolipids (GSLs) and leading to their CD1d-mediated depletion of iNKT cells in vitro and in vivo. IFN-α receptor blockade could reverse the loss of iNKT cells. Excessive stimulation of B cells with IFN-α altered the expression of enzymes that catalyze critical steps in GSL processing, increasing the expressions of glucosylceramide synthase (GCS) and globotrihexosylceramide synthase (Gb3S) but decreasing that of α-galactosidase A (α-galA). Inhibiting GCS or restoring α-galA expression prevented iNKT depletion by IFN-α-activated B cells. Taken together, our work indicated that excessive IFN-α perturbs GSL metabolism in B cells which in turn adversely affects iNKT homeostasis.
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Affiliation(s)
- Andy Hee-Meng Tan
- Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore.
| | - Arleen Sanny
- Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore
| | - Sze-Wai Ng
- Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore
| | - Ying-Swan Ho
- Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore
| | - Nurhidayah Basri
- Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore
| | - Alison Ping Lee
- Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore
| | - Kong-Peng Lam
- Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 11799, Singapore; Department of Microbiology, and Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore; Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.
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11
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Saroha A, Pewzner-Jung Y, Ferreira NS, Sharma P, Jouan Y, Kelly SL, Feldmesser E, Merrill AH, Trottein F, Paget C, Lang KS, Futerman AH. Critical Role for Very-Long Chain Sphingolipids in Invariant Natural Killer T Cell Development and Homeostasis. Front Immunol 2017; 8:1386. [PMID: 29163475 PMCID: PMC5672022 DOI: 10.3389/fimmu.2017.01386] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Accepted: 10/09/2017] [Indexed: 12/14/2022] Open
Abstract
The role of sphingolipids (SLs) in the immune system has come under increasing scrutiny recently due to the emerging contributions that these important membrane components play in regulating a variety of immunological processes. The acyl chain length of SLs appears particularly critical in determining SL function. Here, we show a role for very-long acyl chain SLs (VLC-SLs) in invariant natural killer T (iNKT) cell maturation in the thymus and homeostasis in the liver. Ceramide synthase 2-null mice, which lack VLC-SLs, were susceptible to a hepatotropic strain of lymphocytic choriomeningitis virus, which is due to a reduction in the number of iNKT cells. Bone marrow chimera experiments indicated that hematopoietic-derived VLC-SLs are essential for maturation of iNKT cells in the thymus, whereas parenchymal-derived VLC-SLs are crucial for iNKT cell survival and maintenance in the liver. Our findings suggest a critical role for VLC-SL in iNKT cell physiology.
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Affiliation(s)
- Ashish Saroha
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Yael Pewzner-Jung
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Natalia S Ferreira
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Piyush Sharma
- Medical Faculty, Institute of Immunology, University Duisburg-Essen, Essen, Germany
| | - Youenn Jouan
- INSERM U1100, Centre d'Etude des Pathologies Respiratoires, Faculté de Médecine, Tours, France
| | - Samuel L Kelly
- School of Biology and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, United States
| | - Ester Feldmesser
- Life Science Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Alfred H Merrill
- School of Biology and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, United States
| | - François Trottein
- Centre d'Infection et d'Immunité de Lille, INSERM U1019, CNRS UMR 8204, University of Lille, CHU Lille- Institut Pasteur de Lille, Lille, France
| | - Christophe Paget
- INSERM U1100, Centre d'Etude des Pathologies Respiratoires, Faculté de Médecine, Tours, France.,Centre d'Infection et d'Immunité de Lille, INSERM U1019, CNRS UMR 8204, University of Lille, CHU Lille- Institut Pasteur de Lille, Lille, France
| | - Karl S Lang
- Medical Faculty, Institute of Immunology, University Duisburg-Essen, Essen, Germany
| | - Anthony H Futerman
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
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12
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Meyer B, Groseth A. Apoptosis during arenavirus infection: mechanisms and evasion strategies. Microbes Infect 2017; 20:65-80. [PMID: 29081359 DOI: 10.1016/j.micinf.2017.10.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 10/15/2017] [Accepted: 10/16/2017] [Indexed: 11/17/2022]
Abstract
In recent years there has been a greatly increased interest in the interactions of arenaviruses with the apoptotic machinery, and particularly the extent to which these interactions may be an important contributor to pathogenesis. Here we summarize the current state of our knowledge on this subject and address the potential for interplay with other immunological mechanisms known to be regulated by these viruses. We also compare and contrast what is known for arenavirus-induced apoptosis with observations from other segmented hemorrhagic fever viruses.
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Affiliation(s)
- Bjoern Meyer
- Viral Populations and Pathogenesis Unit, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France.
| | - Allison Groseth
- Friedrich-Loeffler-Institut, Südufer 10, 17493 Greifswald - Insel Riems, Germany
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13
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Littwitz-Salomon E, Schimmer S, Dittmer U. Natural killer T cells contribute to the control of acute retroviral infection. Retrovirology 2017; 14:5. [PMID: 28122574 PMCID: PMC5267384 DOI: 10.1186/s12977-017-0327-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 01/03/2017] [Indexed: 01/12/2023] Open
Abstract
Background Natural killer T cells (NKT cells) play an important role in the immunity against viral infections. They produce cytokines or have direct cytolytic effects that can restrict virus replication. However, the exact function of NKT cells in retroviral immunity is not fully elucidated. Therefore, we analyzed the antiretroviral functions of NKT cells in mice infected with the Friend retrovirus (FV). Results After FV infection numbers of NKT cells remained unchanged but activation as well as improved effector functions of NKT cells were found. While the release of pro-inflammatory cytokines was not changed after infection, activated NKT cells revealed an elevated cytotoxic potential. Stimulation with α-Galactosylceramide significantly increased not only total NKT cell numbers and activation but also the anti-retroviral capacity of NKT cells. Conclusion We demonstrate a strong activation and a potent cytolytic function of NKT cells during acute retroviral infection. Therapeutic treatment with α-Galactosylceramide could further improve the reduction of early retroviral replication by NKT cells, which could be utilized for future treatment against viral infections. Electronic supplementary material The online version of this article (doi:10.1186/s12977-017-0327-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Elisabeth Littwitz-Salomon
- Institute for Virology of the University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.
| | - Simone Schimmer
- Institute for Virology of the University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany
| | - Ulf Dittmer
- Institute for Virology of the University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany
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14
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Fahrner R, Dondorf F, Ardelt M, Settmacher U, Rauchfuss F. Role of NK, NKT cells and macrophages in liver transplantation. World J Gastroenterol 2016; 22:6135-6144. [PMID: 27468206 PMCID: PMC4945975 DOI: 10.3748/wjg.v22.i27.6135] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/25/2016] [Accepted: 06/15/2016] [Indexed: 02/07/2023] Open
Abstract
Liver transplantation has become the treatment of choice for acute or chronic liver disease. Because the liver acts as an innate immunity-dominant organ, there are immunological differences between the liver and other organs. The specific features of hepatic natural killer (NK), NKT and Kupffer cells and their role in the mechanism of liver transplant rejection, tolerance and hepatic ischemia-reperfusion injury are discussed in this review.
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15
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Webb TJ, Carey GB, East JE, Sun W, Bollino DR, Kimball AS, Brutkiewicz RR. Alterations in cellular metabolism modulate CD1d-mediated NKT-cell responses. Pathog Dis 2016; 74:ftw055. [PMID: 27297969 DOI: 10.1093/femspd/ftw055] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2016] [Indexed: 01/27/2023] Open
Abstract
Natural killer T (NKT) cells play a critical role in the host's innate immune response. CD1d-mediated presentation of glycolipid antigens to NKT cells has been established; however, the mechanisms by which NKT cells recognize infected or cancerous cells remain unclear. 5(')-AMP activated protein kinase (AMPK) is a master regulator of lipogenic pathways. We hypothesized that activation of AMPK during infection and malignancy could alter the repertoire of antigens presented by CD1d and serve as a danger signal to NKT cells. In this study, we examined the effect of alterations in metabolism on CD1d-mediated antigen presentation to NKT cells and found that an infection with lymphocytic choriomeningitis virus rapidly increased CD1d-mediated antigen presentation. Hypoxia inducible factors (HIF) enhance T-cell effector functions during infection, therefore antigen presenting cells pretreated with pharmacological agents that inhibit glycolysis, induce HIF and activate AMPK were assessed for their ability to induce NKT-cell responses. Pretreatment with 2-deoxyglucose, cobalt chloride, AICAR and metformin significantly enhanced CD1d-mediated NKT-cell activation. In addition, NKT cells preferentially respond to malignant B cells and B-cell lymphomas express HIF-1α. These data suggest that targeting cellular metabolism may serve as a novel means of inducing innate immune responses.
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Affiliation(s)
- Tonya J Webb
- Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA
| | - Gregory B Carey
- Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA
| | - James E East
- Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA
| | - Wenji Sun
- Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA
| | - Dominique R Bollino
- Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA
| | - Amy S Kimball
- Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA
| | - Randy R Brutkiewicz
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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16
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Hao YE, He DF, Yin RH, Chen H, Wang J, Wang SX, Zhan YQ, Ge CH, Li CY, Yu M, Yang XM. GIT2 deficiency attenuates concanavalin A-induced hepatitis in mice. FEBS Open Bio 2015; 5:688-704. [PMID: 26380813 PMCID: PMC4556731 DOI: 10.1016/j.fob.2015.08.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Revised: 08/06/2015] [Accepted: 08/07/2015] [Indexed: 12/29/2022] Open
Abstract
GIT2 depletion attenuates Con A-induced immunological hepatic injuries. GIT2 depletion suppressed the activation and function of mouse CD4+ T cells. GIT2 depletion suppressed liver infiltration by lymphoid cells after Con A treatment. There were lower levels of proinflammatory cytokines in Git2−/− mice after Con A injection. G protein-coupled receptor kinase interactor 2 (GIT2) is a signaling scaffold protein involved in regulation of cytoskeletal dynamics and the internalization of G protein-coupled receptors (GPCRs). The short-splice form of GIT2 is expressed in peripheral T cells and thymocytes. However, the functions of GIT2 in T cells have not yet been determined. We show that treatment with Con A in a model of polyclonal T-lymphocyte activation resulted in marked inhibitions in the intrahepatic infiltration of inflammatory cells, cytokine response and acute liver failure in Git2−/− mice. CD4+ T cells from Git2−/− mice showed significant impairment in proliferation, cytokine production and signal transduction upon TCR-stimulated activation. Our results suggested that GIT2 plays an important role in T-cell function in vivo and in vitro.
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Affiliation(s)
- Yu-E Hao
- Southern Medical University, Guangzhou, Guangdong Province, China ; State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Dong-Fang He
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China ; Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Rong-Hua Yin
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Hui Chen
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Jian Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Shao-Xia Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Yi-Qun Zhan
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Chang-Hui Ge
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Chang-Yan Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Miao Yu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Xiao-Ming Yang
- Southern Medical University, Guangzhou, Guangdong Province, China ; State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China ; Anhui Medical University, Hefei 230032, Anhui Province, China
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17
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Van Kaer L, Parekh VV, Wu L. The Response of CD1d-Restricted Invariant NKT Cells to Microbial Pathogens and Their Products. Front Immunol 2015; 6:226. [PMID: 26029211 PMCID: PMC4429631 DOI: 10.3389/fimmu.2015.00226] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 04/27/2015] [Indexed: 12/18/2022] Open
Abstract
Invariant natural killer T (iNKT) cells become activated during a wide variety of infections. This includes organisms lacking cognate CD1d-binding glycolipid antigens recognized by the semi-invariant T cell receptor of iNKT cells. Additional studies have shown that iNKT cells also become activated in vivo in response to microbial products such as bacterial lipopolysaccharide, a potent inducer of cytokine production in antigen-presenting cells (APCs). Other studies have shown that iNKT cells are highly responsive to stimulation by cytokines such as interleukin-12. These findings have led to the concept that microbial pathogens can activate iNKT cells either directly via glycolipids or indirectly by inducing cytokine production in APCs. iNKT cells activated in this manner produce multiple cytokines that can influence the outcome of infection, usually in favor of the host, although potent iNKT cell activation may contribute to an uncontrolled cytokine storm and sepsis. One aspect of the response of iNKT cells to microbial pathogens is that it is short-lived and followed by an extended time period of unresponsiveness to reactivation. This refractory period may represent a means to avoid chronic activation and cytokine production by iNKT cells, thus protecting the host against some of the negative effects of iNKT cell activation, but potentially putting the host at risk for secondary infections. These effects of microbial pathogens and their products on iNKT cells are not only important for understanding the role of these cells in immune responses against infections but also for the development of iNKT cell-based therapies.
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Affiliation(s)
- Luc Van Kaer
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine , Nashville, TN , USA
| | - Vrajesh V Parekh
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine , Nashville, TN , USA
| | - Lan Wu
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine , Nashville, TN , USA
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18
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Long J, Zhou B, Li H, Dai Q, Zhang B, Xing S, Zeng Z, Chen W, Yang J. Improvement of HBsAg gene-modified dendritic cell-based vaccine efficacy by optimizing immunization method or the application of β-glucosylceramide. Immunol Invest 2013; 42:137-55. [PMID: 23323523 DOI: 10.3109/08820139.2012.744418] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Hepatocellular carcinoma (HCC) in China is mostly Hepatitis B virus infection related. The antitumor efficacy of HBsAg gene-modified dendritic cells (DC) has been widely tested both in vitro and in vivo. In this study, we analyzed whether adenoviral vector mediated HBsAg expression would alter cell surface phenotype or autologous T cell stimulating function of mature DCs. Further, the anti-tumor efficacy of pAd-HBsAg-DC-based vaccine was evaluated in mice bearing HBsAg expressing HCC. We also tested whether β-glucosylceramide (β-GC) would enhance the anti-tumor activity of pAd-HBsAg-DC. Results revealed that pAd-HBsAg-DC expressed and secreted HBsAg, while maintaining phenotypic characteristics of mature DCs. Vaccination with pAd-HBsAg-DC conferred specific therapeutic antitumor immunity to animal model bearing HBsAg expressing HCC. The application of β-GC activated mice hepatic NKT cells and enhanced the antitumor activity of pAd-HBsAg-DC. Most importantly, in vivo results showed that the inhibiting effect of pAd-HBsAg-DC vaccination on tumor growth was more significant when applied before tumor inoculation, suggesting that genetically modified DC based therapeutic cancer vaccine may achieve the most optimized antitumor effect when applied before tumor onset, and β-GC may serve as a potent innate immune enhancer for augmenting the antitumor effect of pAd-HBsAg-DC vaccine.
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Affiliation(s)
- Jianting Long
- Department of Medicinal Oncology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, PR China
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19
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Wehr A, Baeck C, Heymann F, Niemietz PM, Hammerich L, Martin C, Zimmermann HW, Pack O, Gassler N, Hittatiya K, Ludwig A, Luedde T, Trautwein C, Tacke F. Chemokine receptor CXCR6-dependent hepatic NK T Cell accumulation promotes inflammation and liver fibrosis. THE JOURNAL OF IMMUNOLOGY 2013; 190:5226-36. [PMID: 23596313 DOI: 10.4049/jimmunol.1202909] [Citation(s) in RCA: 202] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chronic liver injury characteristically results in hepatic inflammation, which represents a prerequisite for organ fibrosis. Although NKT cells are abundantly present in liver and involved in hepatic inflammation, molecular mechanisms of their recruitment in liver fibrosis remained elusive. We hypothesized that chemokine receptor CXCR6 and its ligand CXCL16 control NKT cell migration and functionality in liver fibrosis. In patients with chronic liver diseases (n = 58), CXCR6 and CXCL16 expression was intrahepatically upregulated compared with controls. In murine liver, Cxcl16 was strongly expressed by endothelium and macrophages, whereas lymphocyte populations (NKT, NK, CD4 T, CD8 T cells) expressed CXCR6. Intravital two-photon microscopy imaging of Cxcr6(+/gfp) and Cxcr6(gfp/gfp) mice and chemotaxis studies in vitro revealed that CXCR6 specifically controls hepatic NKT cell accumulation during the early response upon experimental liver damage. Hepatic invariant NKT cells expressed distinct proinflammatory cytokines including IFN-γ and IL-4 upon injury. CXCR6-deficient mice were protected from liver fibrosis progression in two independent experimental models. Macrophage infiltration and protein levels of inflammatory cytokines IFN-γ, TNF-α, and IL-4 were also reduced in fibrotic livers of Cxcr6(-/-) mice, corroborating that hepatic NKT cells provide essential cytokine signals perpetuating hepatic inflammation and fibrogenesis. Adoptive transfer of NKT cells, but not CD4 T cells, isolated from wild type livers restored hepatic fibrosis in Cxcr6(-/-) mice upon experimental steatohepatitis. Our results demonstrate that hepatic NKT cells accumulate CXCR6-dependent early upon injury, thereby accentuating the inflammatory response in the liver and promoting hepatic fibrogenesis. Interfering with CXCR6/CXCL16 might therefore bear therapeutic potential in liver fibrosis.
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Affiliation(s)
- Alexander Wehr
- Department of Medicine III, University-Hospital Aachen, 52074 Aachen, Germany
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20
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Wakabayashi H, Ito T, Fushimi S, Nakashima Y, Itakura J, Qiuying L, Win MM, Cuiming S, Chen C, Sato M, Mino M, Ogino T, Makino H, Yoshimura A, Matsukawa A. Spred-2 deficiency exacerbates acetaminophen-induced hepatotoxicity in mice. Clin Immunol 2012; 144:272-82. [PMID: 22868447 DOI: 10.1016/j.clim.2012.07.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2012] [Revised: 06/30/2012] [Accepted: 07/03/2012] [Indexed: 02/06/2023]
Abstract
MAPKs are involved in acetaminophen (APAP)-hepatotoxicity, but the regulatory mechanism remains unknown. Here, we explored the role of Spred-2 that negatively regulates Ras/ERK pathway in APAP-hepatotoxicity. Spred-2 knockout (KO) mice demonstrated exacerbated liver injury, an event that was associated with increased numbers of CD4(+) T, CD8(+) T and NK cells in the liver compared to the control. Levels of CXCL9/CXCL10 that attract and activate these cells were increased in Spred-2 KO-liver. Kupffer cells isolated from Spred-2 KO mice after APAP challenge expressed higher levels of CXCL9/CXCL10 than those from the control. Upon stimulation with APAP or IFNγ, naïve Kupffer cells from Spred-2 KO mice expressed higher levels of CXCL9/CXCL10. NK cell-depletion attenuated APAP-hepatotoxicity with lowered hepatic IFNγ and decreased numbers of not only NK cells but also CD4(+) T and CD8(+) T cells in the liver. These results suggest that Spred-2 negatively regulates APAP-hepatotoxicity under the control of Kupffer cells and NK cells.
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Affiliation(s)
- Hiroshi Wakabayashi
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Japan
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21
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Ivanov S, Fontaine J, Paget C, Macho Fernandez E, Van Maele L, Renneson J, Maillet I, Wolf NM, Rial A, Léger H, Ryffel B, Frisch B, Chabalgoity JA, Sirard JC, Benecke A, Faveeuw C, Trottein F. Key role for respiratory CD103(+) dendritic cells, IFN-γ, and IL-17 in protection against Streptococcus pneumoniae infection in response to α-galactosylceramide. J Infect Dis 2012; 206:723-34. [PMID: 22723642 DOI: 10.1093/infdis/jis413] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Exogenous activation of pulmonary invariant natural killer T (iNKT) cells, a population of lipid-reactive αβ T lymphocytes, with use of mucosal α-galactosylceramide (α-GalCer) administration, is a promising approach to control respiratory bacterial infections. We undertook the present study to characterize mechanisms leading to α-GalCer-mediated protection against lethal infection with Streptococcus pneumoniae serotype 1, a major respiratory pathogen in humans. METHODS AND RESULTS α-GalCer was administered by the intranasal route before infection with S. pneumoniae. We showed that respiratory dendritic cells (DCs), most likely the CD103(+) subset, play a major role in the activation (IFN-γ and IL-17 release) of pulmonary iNKT cells, whereas alveolar and interstitial macrophages are minor players. After challenge, S. pneumoniae was rapidly (4 hours) eliminated in the alveolar spaces, a phenomenon that depended on respiratory DCs and neutrophils, but not macrophages, and on the early production of both IFN-γ and IL-17. Protection was also associated with the synthesis of various interferon-dependent and IL-17-associated genes as revealed by transcriptomic analysis. CONCLUSIONS These data imply a new function for pulmonary CD103(+) DCs in mucosal activation of iNKT cells and establish a critical role for both IFN-γ and IL-17 signalling pathways in mediating the innate immune response to S. pneumoniae.
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Affiliation(s)
- Stoyan Ivanov
- Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, France
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22
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Downs I, Liu J, Aw TY, Adegboyega PA, Ajuebor MN. The ROS scavenger, NAC, regulates hepatic Vα14iNKT cells signaling during Fas mAb-dependent fulminant liver failure. PLoS One 2012; 7:e38051. [PMID: 22701598 PMCID: PMC3368940 DOI: 10.1371/journal.pone.0038051] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Accepted: 05/02/2012] [Indexed: 01/28/2023] Open
Abstract
Uncontrolled systemic activation of the immune system is an early initiating event that leads to development of acute fulminant liver failure (FLF) in mice after treatment with agonistic Fas mAb. In this study, we demonstrate that treatment of mice with N-acetylcysteine (NAC), an ROS scavenger and glutathione (GSH) precursor, almost completely abolished Fas mAb-induced FLF through suppression of Vα14iNKT cell activation, IFN-γ signaling, apoptosis and nitrotyrosine formation in liver. In addition, enrichment of the liver with GSH due to Vα14iNKT cells deficiency, induced an anti-inflammatory response in the liver of Jα18(-/-) mice that inhibited apoptosis, nitrotyrosine formation, IFN-γ signaling and effector functions. In summary, we propose a novel and previously unrecognized pro-inflammatory and pro-apoptotic role for endogenous ROS in stimulating Th1 signaling in Vα14iNKT cells to promote the development of FLF. Therefore, our study provides critical new insights into how NAC, a ROS scavenger, regulates Th1 signaling in intrahepatic Vα14iNKT cells to impact inflammatory and pathological responses.
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Affiliation(s)
- Isaac Downs
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
| | - Jianfeng Liu
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
| | - Tak Yee Aw
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
| | - Patrick A. Adegboyega
- Department of Pathology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
| | - Maureen N. Ajuebor
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America
- * E-mail:
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Costimulatory activation of murine invariant natural killer T cells by toll-like receptor agonists. Cell Immunol 2012; 277:33-43. [DOI: 10.1016/j.cellimm.2012.06.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Accepted: 06/04/2012] [Indexed: 12/11/2022]
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Paget C, Ivanov S, Fontaine J, Renneson J, Blanc F, Pichavant M, Dumoutier L, Ryffel B, Renauld JC, Gosset P, Gosset P, Si-Tahar M, Faveeuw C, Trottein F. Interleukin-22 is produced by invariant natural killer T lymphocytes during influenza A virus infection: potential role in protection against lung epithelial damages. J Biol Chem 2012; 287:8816-29. [PMID: 22294696 PMCID: PMC3308738 DOI: 10.1074/jbc.m111.304758] [Citation(s) in RCA: 147] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2011] [Revised: 01/17/2012] [Indexed: 12/25/2022] Open
Abstract
Invariant natural killer T (iNKT) cells are non-conventional lipid-reactive αβ T lymphocytes that play a key role in host responses during viral infections, in particular through the swift production of cytokines. Their beneficial role during experimental influenza A virus (IAV) infection has recently been proposed, although the mechanisms involved remain elusive. Here we show that during in vivo IAV infection, mouse pulmonary iNKT cells produce IFN-γ and IL-22, a Th17-related cytokine critical in mucosal immunity. Although permissive to viral replication, IL-22 production by iNKT cells is not due to IAV infection per se of these cells but is indirectly mediated by IAV-infected dendritic cells (DCs). We show that activation of the viral RNA sensors TLR7 and RIG-I in DCs is important for triggering IL-22 secretion by iNKT cells, whereas the NOD-like receptors NOD2 and NLRP3 are dispensable. Invariant NKT cells respond to IL-1β and IL-23 provided by infected DCs independently of the CD1d molecule to release IL-22. In vitro, IL-22 protects IAV-infected airway epithelial cells against mortality but has no role on viral replication. Finally, during early IAV infection, IL-22 plays a positive role in the control of lung epithelial damages. Overall, IAV infection of DCs activates iNKT cells, providing a rapid source of IL-22 that might be beneficial to preserve the lung epithelium integrity.
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Affiliation(s)
- Christophe Paget
- From the Institut Pasteur de Lille, Center for Infection and Immunity of Lille, F-59019 Lille, France
- Université Lille Nord de France, F-59000 Lille, France
- CNRS, UMR 8204, F-59021 Lille France
- Institut National de la Santé et de la Recherche Médicale, U1019, F-59019 Lille, France
- Institut Fédératif de Recherche 142, F-59019 Lille, France
| | - Stoyan Ivanov
- From the Institut Pasteur de Lille, Center for Infection and Immunity of Lille, F-59019 Lille, France
- Université Lille Nord de France, F-59000 Lille, France
- CNRS, UMR 8204, F-59021 Lille France
- Institut National de la Santé et de la Recherche Médicale, U1019, F-59019 Lille, France
- Institut Fédératif de Recherche 142, F-59019 Lille, France
| | - Josette Fontaine
- From the Institut Pasteur de Lille, Center for Infection and Immunity of Lille, F-59019 Lille, France
- Université Lille Nord de France, F-59000 Lille, France
- CNRS, UMR 8204, F-59021 Lille France
- Institut National de la Santé et de la Recherche Médicale, U1019, F-59019 Lille, France
- Institut Fédératif de Recherche 142, F-59019 Lille, France
| | - Joelle Renneson
- From the Institut Pasteur de Lille, Center for Infection and Immunity of Lille, F-59019 Lille, France
- Université Lille Nord de France, F-59000 Lille, France
- CNRS, UMR 8204, F-59021 Lille France
- Institut National de la Santé et de la Recherche Médicale, U1019, F-59019 Lille, France
- Institut Fédératif de Recherche 142, F-59019 Lille, France
| | - Fany Blanc
- Institut Pasteur, F-75015 Paris, France
- Institut National de la Santé et de la Recherche Médicale, U874, F-75015 Paris, France
| | - Muriel Pichavant
- From the Institut Pasteur de Lille, Center for Infection and Immunity of Lille, F-59019 Lille, France
- Université Lille Nord de France, F-59000 Lille, France
- CNRS, UMR 8204, F-59021 Lille France
- Institut National de la Santé et de la Recherche Médicale, U1019, F-59019 Lille, France
- Institut Fédératif de Recherche 142, F-59019 Lille, France
| | - Laure Dumoutier
- Ludwig Institute for Cancer Research, Université Catholique de Louvain, 1200 Brussels, Belgium
| | - Bernhard Ryffel
- CNRS, UMR 6218, Molecular Immunology and Embryology, Université d'Orléans, 45071 Orléans, France, and
| | - Jean Christophe Renauld
- Ludwig Institute for Cancer Research, Université Catholique de Louvain, 1200 Brussels, Belgium
| | - Philippe Gosset
- From the Institut Pasteur de Lille, Center for Infection and Immunity of Lille, F-59019 Lille, France
- Université Lille Nord de France, F-59000 Lille, France
- CNRS, UMR 8204, F-59021 Lille France
- Institut National de la Santé et de la Recherche Médicale, U1019, F-59019 Lille, France
- Institut Fédératif de Recherche 142, F-59019 Lille, France
| | - Pierre Gosset
- Hopital Saint Vincent, Groupe Hospitalier de l'Institut Catholique de Lille, Université Catholique de Lille, F-59020 Lille, France
| | - Mustapha Si-Tahar
- Institut Pasteur, F-75015 Paris, France
- Institut National de la Santé et de la Recherche Médicale, U874, F-75015 Paris, France
| | - Christelle Faveeuw
- From the Institut Pasteur de Lille, Center for Infection and Immunity of Lille, F-59019 Lille, France
- Université Lille Nord de France, F-59000 Lille, France
- CNRS, UMR 8204, F-59021 Lille France
- Institut National de la Santé et de la Recherche Médicale, U1019, F-59019 Lille, France
- Institut Fédératif de Recherche 142, F-59019 Lille, France
| | - François Trottein
- From the Institut Pasteur de Lille, Center for Infection and Immunity of Lille, F-59019 Lille, France
- Université Lille Nord de France, F-59000 Lille, France
- CNRS, UMR 8204, F-59021 Lille France
- Institut National de la Santé et de la Recherche Médicale, U1019, F-59019 Lille, France
- Institut Fédératif de Recherche 142, F-59019 Lille, France
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V. Nuvor S, Whittle H, Rowland-Jones S, Jaye A. Greater Expansion of IFN-<i>γ</i><sup>﹣</sup> CD4<sup>+</sup> NKT Cells in HIV-1 Compared with HIV-2-Infected Subjects with Preserved CD4<sup>+</sup> T Cell Counts. ACTA ACUST UNITED AC 2012. [DOI: 10.4236/wja.2012.22014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Chen L, Jay DC, Fairbanks JD, He X, Jensen PE. An MHC class Ib-restricted CD8+ T cell response to lymphocytic choriomeningitis virus. THE JOURNAL OF IMMUNOLOGY 2011; 187:6463-72. [PMID: 22084437 DOI: 10.4049/jimmunol.1101171] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Conventional MHC class Ia-restricted CD8(+) T cells play a dominant role in the host response to virus infections, but recent studies indicate that T cells with specificity for nonclassical MHC class Ib molecules may also participate in host defense. To investigate the potential role of class Ib molecules in anti-viral immune responses, K(b-/-)D(b-/-)CIITA(-/-) mice lacking expression of MHC class Ia and class II molecules were infected with lymphocytic choriomeningitis virus (LCMV). These animals have a large class Ib-selected CD8(+) T cell population and they were observed to mediate partial (but incomplete) virus clearance during acute LCMV infection as compared with K(b-/-)D(b-/-)β(2)-microglobulin(-/-) mice that lack expression of both MHC class Ia and class Ib molecules. Infection was associated with expansion of splenic CD8(+) T cells and induction of granzyme B and IFN-γ effector molecules in CD8(+) T cells. Partial virus clearance was dependent on CD8(+) cells. In vitro T cell restimulation assays demonstrated induction of a population of β(2)-microglobulin-dependent, MHC class Ib-restricted CD8(+) T cells with specificity for viral Ags and yet to be defined nonclassical MHC molecules. MHC class Ib-restricted CD8(+) T cell responses were also observed after infection of K(b-/-)D(b-/-)mice despite the low number of CD8(+) T cells in these animals. Long-term infection studies demonstrated chronic infection and gradual depletion of CD8(+) T cells in K(b-/-)D(b-/-)CIITA(-/-) mice, demonstrating that class Ia molecules are required for viral clearance. These findings demonstrate that class Ib-restricted CD8(+) T cells have the potential to participate in the host immune response to LCMV.
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Affiliation(s)
- Lili Chen
- Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA
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Renneson J, Guabiraba R, Maillet I, Marques RE, Ivanov S, Fontaine J, Paget C, Quesniaux V, Faveeuw C, Ryffel B, Teixeira MM, Trottein F. A detrimental role for invariant natural killer T cells in the pathogenesis of experimental dengue virus infection. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 179:1872-83. [PMID: 21843496 DOI: 10.1016/j.ajpath.2011.06.023] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Revised: 05/27/2011] [Accepted: 06/09/2011] [Indexed: 01/12/2023]
Abstract
Dengue virus (DENV), a member of the mosquito-borne flaviviruses, is a serious public health problem in many tropical countries. We assessed the in vivo physiologic contribution of invariant natural killer T (iNKT) cells, a population of nonconventional lipid-reactive αβ T lymphocytes, to the host response during experimental DENV infection. We used a mouse-adapted DENV serotype 2 strain that causes a disease that resembles severe dengue in humans. On DENV challenge, splenic and hepatic iNKT cells became activated insofar as CD69 and Fas ligand up-regulation and interferon-γ production. C57BL/6 mice deficient in iNKT cells (Jα18(-/-)) were more resistant to lethal infection than were wild-type animals, and the phenotype was reversed by adoptive transfer of iNKT cells to Jα18(-/-) animals. The absence of iNKT cells in Jα18(-/-) mice was associated with decreased systemic and local inflammatory responses, less liver injury, diminished vascular leak syndrome, and reduced activation of natural killer cells and neutrophils. iNKT cell functions were not necessary for control of primary DENV infection, after either natural endogenous activation or exogenous activation with the canonical iNKT cell agonist α-galactosylceramide. Together, these data reveal a novel and critical role for iNKT cells in the pathogenesis of severe experimental dengue disease.
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Affiliation(s)
- Joelle Renneson
- Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; Université Lille Nord de France, Lille, France
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28
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Subleski JJ, Hall VL, Wolfe TB, Scarzello AJ, Weiss JM, Chan T, Hodge DL, Back TC, Ortaldo JR, Wiltrout RH. TCR-dependent and -independent activation underlie liver-specific regulation of NKT cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2011; 186:838-47. [PMID: 21148802 PMCID: PMC3725575 DOI: 10.4049/jimmunol.1001735] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The fate of invariant NKT (iNKT) cells following activation remains controversial and unclear. We systemically examined how iNKT cells are regulated following TCR-dependent and -independent activation with α-galactosylceramide (αGC) or IL-18 plus IL-12, respectively. Our studies reveal activation by αGC or IL-18 plus IL-12 induced transient depletion of iNKT cells exclusively in the liver that was independent of caspase 3-mediated apoptosis. The loss of iNKT cells was followed by repopulation and expansion of phenotypically distinct cells via different mechanisms. Liver iNKT cell expansion following αGC, but not IL-18 plus IL-12, treatment required an intact spleen and IFN-γ. Additionally, IL-18 plus IL-12 induced a more prolonged expansion of liver iNKT cells compared with αGC. iNKT cells that repopulate the liver following αGC had higher levels of suppressive receptors PD-1 and Lag3, whereas those that repopulate the liver following IL-18 plus IL-12 had increased levels of TCR and ICOS. In contrast to acute treatment that caused a transient loss of iNKT cells, chronic αGC or IL-18 plus IL-12 treatment caused long-term systemic loss requiring an intact thymus for repopulation of the liver. This report reveals a previously undefined role for the liver in the depletion of activated iNKT cells. Additionally, TCR-dependent and -independent activation differentially regulate iNKT cell distribution and phenotype. These results provide new insights for understanding how iNKT cells are systemically regulated following activation.
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Affiliation(s)
- Jeff J. Subleski
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick MD, USA 21702
| | - Veronica L. Hall
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick MD, USA 21702
| | - Thomas B. Wolfe
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick MD, USA 21702
| | - Anthony J. Scarzello
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick MD, USA 21702
| | - Jonathan M. Weiss
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick MD, USA 21702
| | - Tim Chan
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick MD, USA 21702
| | - Deborah L. Hodge
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick MD, USA 21702
| | - Timothy C. Back
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick MD, USA 21702
| | - John R. Ortaldo
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick MD, USA 21702
| | - Robert H. Wiltrout
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick MD, USA 21702
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Schneiders FL, Scheper RJ, von Blomberg BME, Woltman AM, Janssen HLA, van den Eertwegh AJM, Verheul HMW, de Gruijl TD, van der Vliet HJ. Clinical experience with α-galactosylceramide (KRN7000) in patients with advanced cancer and chronic hepatitis B/C infection. Clin Immunol 2010; 140:130-41. [PMID: 21169066 DOI: 10.1016/j.clim.2010.11.010] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Revised: 11/12/2010] [Accepted: 11/16/2010] [Indexed: 01/12/2023]
Abstract
For over a century, research has sought ways to boost the immune system in order to eradicate tumors and viruses that exist after escaping immunosurveillance. For the treatment of cancer and hepatitis immunotherapeutic strategies have overall had limited clinical success. An urgent need exists therefore to introduce more effective therapeutic approaches. Invariant (i)NKT cells constitute a conserved T lymphocyte lineage with dominant immunoregulatory, antitumor and antiviral effector cell properties. iNKT specifically recognize the glycolipid α-galactosylceramide in the context of CD1d resulting in their activation. Activated iNKT can promote the development of a long-lasting Th1 biased proinflammatory immune response as demonstrated in multiple tumor-metastasis and viral infection models. Here, we will provide a brief overview of the preclinical data of α-galactosylceramide that formed the basis for subsequent clinical trials in patients with advanced cancer and chronic hepatitis B/C, and elaborate on our own clinical experience with α-galactosylceramide in these patient groups.
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Affiliation(s)
- Famke L Schneiders
- Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
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Kulkarni RR, Haeryfar SM, Sharif S. The invariant NKT cell subset in anti-viral defenses: a dark horse in anti-influenza immunity? J Leukoc Biol 2010; 88:635-643. [PMID: 20519638 DOI: 10.1189/jlb.0410191] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
iNKT cells, a small subset of αβ TCR+ T cells, are capable of producing large amounts of cytokines upon activation through their TCR. Unlike conventional T cells that express highly diverse TCRs, iNKT cells express a glycolipid-reactive invariant TCR-α chain paired with a limited number of β chain(s). These cells recognize glycolipid antigens when presented on CD1d molecules found on APC or other cells. Although the immunoregulatory roles of iNKT cells in the context of autoimmune disease are fairly well characterized, several lines of evidence highlight the importance of this cell type in immune responses against microbial insults caused by bacterial, viral, and parasitic pathogens. Recent studies that have investigated the role of iNKT cells in immune responses against influenza virus have suggested an important role for these cells in innate defense mechanisms as well as antibody- and cell-mediated responses. This review highlights the important contributions of iNKT cells to immune responses against viral pathogens with particular emphasis on immunity to influenza infections.
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Affiliation(s)
- R R Kulkarni
- Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada
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V(alpha)14iNKT cells promote liver pathology during adenovirus infection by inducing CCL5 production: implications for gene therapy. J Virol 2010; 84:8520-9. [PMID: 20573836 DOI: 10.1128/jvi.00605-10] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Replication-defective recombinant adenoviruses are the most widely studied replication-defective vectors for the potential treatment of inherited human diseases. However, broad clinical application of replication-defective adenoviruses in gene therapy is being hindered by the induction of vigorous innate and adaptive immune responses against the vector that cause deleterious effects in the liver. V(alpha)14 invariant natural killer T cells (V(alpha)14iNKT cells) are thymus-derived innate T cells at the interface between the two arms of the immune response and provide full engagement of host defense. The pathophysiological role of intrahepatic V(alpha)14iNKT cells during replication-defective adenovirus infection is not known and is the main focus of our study. Our data showed that intrahepatic V(alpha)14iNKT cells were activated in response to adenovirus infection to induce significant levels of hepatic chemokine (C-C motif) ligand 5 (CCL5) and subsequent liver toxicity. Moreover, intrahepatic CCL5 production was selectively reduced by V(alpha)14iNKT cell deficiency. In vivo studies utilizing CCL5-deficient mice or V(alpha)14iNKT cell-deficient mice demonstrated that CCL5 deficiency or V(alpha)14iNKT cell deficiency was associated with reduced liver pathology. Similar results were seen after blocking the biological effects of the CCL5 receptors. In conclusion, we have identified an important proinflammatory role for activated intrahepatic V(alpha)14iNKT cells in positively influencing hepatic CCL5 production to promote acute liver inflammation and injury. Therefore, our findings highlight the blockade of CCL5 interaction with a cognate receptor(s) as an important potential strategy to alleviate liver pathology associated with replication-defective adenovirus infection.
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Ansari AW, Temblay JN, Alyahya SH, Ashton-Rickardt PG. Serine protease inhibitor 6 protects iNKT cells from self-inflicted damage. THE JOURNAL OF IMMUNOLOGY 2010; 185:877-83. [PMID: 20543105 DOI: 10.4049/jimmunol.1000651] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The role played by apoptosis in the homeostasis of effector cells of the innate immune system is unclear. Serine protease inhibitor 6 (Spi6) is an inhibitor of granzyme B (GrB) that protects cytotoxic T lymphocytes of the adaptive immune system from apoptosis. To determine whether Spi6 also protects cells of the innate immune system from self-inflicted damage we have examined invariant NKT (iNKT) cells. Spi6-deficient iNKT cells harbored increased levels of GrB after TCR stimulation with the PBS-57 glycolipid Ag and were susceptible to apoptosis. The increased apoptosis of Spi6 knock-out (KO) iNKT cells lead to a complete loss in the production of IL-4 and IFN-gamma by Spi6 KO iNKT cells after PBS-57 challenge. The increased activation-induced apoptosis resulted in impaired survival and a decreased clonal burst size of Spi6 KO iNKT cells, which could be corrected by GrB deficiency. However, the clonal burst of Spi6 KO iNKT cells after TCR-independent activation with lymphocytic choriomeningitis virus was not affected. Our findings demonstrate that Spi6 protects cytotoxic cells of the innate immune system from GrB-mediated self-inflicted triggered by the recognition of Ag.
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Affiliation(s)
- A Wahid Ansari
- Section of Immunobiology, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London, United Kingdom
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33
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Yuling H, Ruijing X, Xiang J, Li L, Lang C, Jie X, Wei X, Yujuan W, Lijun Z, Rui Z, Xinti T, Yongyi B, Yan-Ping J, Youxin J, Jinquan T. EBV promotes human CD8 NKT cell development. PLoS Pathog 2010; 6:e1000915. [PMID: 20502687 PMCID: PMC2873918 DOI: 10.1371/journal.ppat.1000915] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2009] [Accepted: 04/20/2010] [Indexed: 12/01/2022] Open
Abstract
The reports on the origin of human CD8+ Vα24+ T-cell receptor (TCR) natural killer T (NKT) cells are controversial. The underlying mechanism that controls human CD4 versus CD8 NKT cell development is not well-characterized. In the present study, we have studied total 177 eligible patients and subjects including 128 healthy latent Epstein-Barr-virus(EBV)-infected subjects, 17 newly-onset acute infectious mononucleosis patients, 16 newly-diagnosed EBV-associated Hodgkin lymphoma patients, and 16 EBV-negative normal control subjects. We have established human-thymus/liver-SCID chimera, reaggregated thymic organ culture, and fetal thymic organ culture. We here show that the average frequency of total and CD8+ NKT cells in PBMCs from 128 healthy latent EBV-infected subjects is significantly higher than in 17 acute EBV infectious mononucleosis patients, 16 EBV-associated Hodgkin lymphoma patients, and 16 EBV-negative normal control subjects. However, the frequency of total and CD8+ NKT cells is remarkably increased in the acute EBV infectious mononucleosis patients at year 1 post-onset. EBV-challenge promotes CD8+ NKT cell development in the thymus of human-thymus/liver-SCID chimeras. The frequency of total (3% of thymic cells) and CD8+ NKT cells (∼25% of NKT cells) is significantly increased in EBV-challenged chimeras, compared to those in the unchallenged chimeras (<0.01% of thymic cells, CD8+ NKT cells undetectable, respectively). The EBV-induced increase in thymic NKT cells is also reflected in the periphery, where there is an increase in total and CD8+ NKT cells in liver and peripheral blood in EBV-challenged chimeras. EBV-induced thymic CD8+ NKT cells display an activated memory phenotype (CD69+CD45ROhiCD161+CD62Llo). After EBV-challenge, a proportion of NKT precursors diverges from DP thymocytes, develops and differentiates into mature CD8+ NKT cells in thymus in EBV-challenged human-thymus/liver-SCID chimeras or reaggregated thymic organ cultures. Thymic antigen-presenting EBV-infected dendritic cells are required for this process. IL-7, produced mainly by thymic dendritic cells, is a major and essential factor for CD8+ NKT cell differentiation in EBV-challenged human-thymus/liver-SCID chimeras and fetal thymic organ cultures. Additionally, these EBV-induced CD8+ NKT cells produce remarkably more perforin than that in counterpart CD4+ NKT cells, and predominately express CD8αα homodimer in their co-receptor. Thus, upon interaction with certain viruses, CD8 lineage-specific NKT cells are developed, differentiated and matured intrathymically, a finding with potential therapeutic importance against viral infections and tumors. We show that the average frequency of total and CD8+ NKT cells in PBMCs from 128 healthy latent EBV-infected subjects is significantly higher than in 17 patients with acute lytic EBV infection, 16 EBV-associated HL patients, and 16 EBV-negative normal subjects. The frequency of total and CD8+ NKT cells is remarkably increased in the lytic EBV-infected patients at year 1 post-onset. EBV-challenge promotes total and CD8+ NKT cell development in the thymus and liver of human-thymus/liver-SCID chimeras, compared to those in the unchallenged chimeras. After EBV-challenge, a proportion of NKT precursors diverges from DP thymocytes, develops and differentiates into mature CD8+ NKT cells in thymus in EBV-challenged human-thymus/liver-SCID chimeras or reaggregated thymic organ cultures. Thymic EBV-infected dendritic cells are required for this process. IL-7 is an essential factor for CD8+ NKT cell differentiation. EBV-induced CD8+ NKT cells produce remarkably more perforin, and predominately express CD8αα homodimer. CD8 lineage-specific NKT cells are developed and differentiated intrathymically upon EBV-exposure, a finding with potential therapeutic importance against viral infections and tumors.
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Affiliation(s)
- He Yuling
- Department of Immunology, Wuhan University School of Medicine, Wuhan, People's Republic of China
- * E-mail: (HY); (TJ)
| | - Xiao Ruijing
- Department of Immunology, Wuhan University School of Medicine, Wuhan, People's Republic of China
| | - Ji Xiang
- Department of Immunology, Wuhan University School of Medicine, Wuhan, People's Republic of China
| | - Li Li
- Department of Immunology, Wuhan University School of Medicine, Wuhan, People's Republic of China
- Laboratory of Allergy and Clinical Immunology, Institute of Allergy and Immune-related Diseases, Centre for Medical Research, Wuhan University School of Medicine, Wuhan, People's Republic of China
| | - Chen Lang
- Department of Immunology, Wuhan University School of Medicine, Wuhan, People's Republic of China
- Laboratory of Allergy and Clinical Immunology, Institute of Allergy and Immune-related Diseases, Centre for Medical Research, Wuhan University School of Medicine, Wuhan, People's Republic of China
| | - Xiong Jie
- Department of Immunology, Wuhan University School of Medicine, Wuhan, People's Republic of China
- Section of Geriatrics, Departments of Internal Medicine, The Renmin University Hospital, Wuhan University, Wuhan, People's Republic of China
| | - Xiao Wei
- Department of Immunology, Wuhan University School of Medicine, Wuhan, People's Republic of China
| | - Wang Yujuan
- Department of Immunology, Wuhan University School of Medicine, Wuhan, People's Republic of China
- Laboratory of Allergy and Clinical Immunology, Institute of Allergy and Immune-related Diseases, Centre for Medical Research, Wuhan University School of Medicine, Wuhan, People's Republic of China
| | - Zhang Lijun
- Section of Geriatrics, Departments of Internal Medicine, The Renmin University Hospital, Wuhan University, Wuhan, People's Republic of China
| | - Zhou Rui
- Department of Immunology, Wuhan University School of Medicine, Wuhan, People's Republic of China
- Laboratory of Allergy and Clinical Immunology, Institute of Allergy and Immune-related Diseases, Centre for Medical Research, Wuhan University School of Medicine, Wuhan, People's Republic of China
| | - Tan Xinti
- Department of Immunology, Wuhan University School of Medicine, Wuhan, People's Republic of China
| | - Bi Yongyi
- Wuhan University School of Public Health, Wuhan, People's Republic of China
| | - Jiang Yan-Ping
- Department of Immunology, Wuhan University School of Medicine, Wuhan, People's Republic of China
| | - Jin Youxin
- The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai, People's Republic of China
| | - Tan Jinquan
- Department of Immunology, Wuhan University School of Medicine, Wuhan, People's Republic of China
- Laboratory of Allergy and Clinical Immunology, Institute of Allergy and Immune-related Diseases, Centre for Medical Research, Wuhan University School of Medicine, Wuhan, People's Republic of China
- * E-mail: (HY); (TJ)
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Rodas JD, Cairo C, Djavani M, Zapata JC, Ruckwardt T, Bryant J, Pauza CD, Lukashevich IS, Salvato MS. Circulating natural killer and gammadelta T cells decrease soon after infection of rhesus macaques with lymphocytic choriomeningitis virus. Mem Inst Oswaldo Cruz 2010; 104:583-91. [PMID: 19722081 DOI: 10.1590/s0074-02762009000400009] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2008] [Accepted: 05/15/2009] [Indexed: 11/22/2022] Open
Abstract
Rhesus macaques infected with the WE strain of lymphocytic choriomeningitis virus (LCMV-WE) serve as a model for human infection with Lassa fever virus. To identify the earliest events of acute infection, rhesus macaques were monitored immediately after lethal infection for changes in peripheral blood mononuclear cells (PBMCs). Changes in CD3, CD4, CD8 and CD20 subsets did not vary outside the normal fluctuations of these blood cell populations; however, natural killer (NK) and gammadelta T cells increased slightly on day 1 and then decreased significantly after two days. The NK subsets responsible for the decrease were primarily CD3-CD8+ or CD3-CD16+ and not the NKT (primarily CD3+CD56+) subset. Macaques infected with a non-virulent arenavirus, LCMV-Armstrong, showed a similar drop in circulating NK and gammadelta T cells, indicating that this is not a pathogenic event. V(3)9 T cells, representing the majority of circulating gammadelta T cells in rhesus macaques, displayed significant apoptosis when incubated with LCMV in cell culture; however, the low amount of cell death for virus-co-cultured NK cells was insufficient to account for the observed disappearance of this subset. Our observations in primates are similar to those seen in LCMV-infected mice, where decreased circulating NK cells were attributed to margination and cell death. Thus, the disappearance of these cells during acute hemorrhagic fever in rhesus macaques may be a cytokine-induced lymphopenia common to many virus infections.
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Affiliation(s)
- Juan D Rodas
- Grupo de Investigaciones en Ciencias Veterinarias Centauro, Facultad de Ciencias Agrarias, Universidad de Antioquia, Medellín, Colombia
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Emoto M, Shimizu T, Koike H, Yoshizawa I, Hurwitz R, Kaufmann SHE, Emoto Y. Dissociated expression of natural killer 1.1 and T-cell receptor by invariant natural killer T cells after interleukin-12 receptor and T-cell receptor signalling. Immunology 2010; 129:62-74. [PMID: 20028429 DOI: 10.1111/j.1365-2567.2009.03148.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Invariant (i) natural killer T (NKT) cells become undetectable after stimulation with alpha-galactosylceramide (alpha-GalCer) or interleukin (IL)-12. Although down-modulation of surface T-cell receptor (TCR)/NKR-P1C (NK1.1) expression has been shown convincingly after stimulation with alpha-GalCer, it is unclear whether this also holds true for IL-12 stimulation. To determine whether failure to detect iNKT cells after IL-12 stimulation is caused by dissociation/internalization of TCR and/or NKR-P1C, or by block of de novo synthesis of these molecules, and to examine the role of IL-12 in the disappearance of iNKT cells after stimulation with alpha-GalCer, surface (s)/cytoplasmic (c) protein expression, as well as messenger RNA (mRNA) expression of TCR/NKR-P1C by iNKT cells after stimulation with alpha-GalCer or IL-12, and the influence of IL-12 neutralization on the down-modulation of sTCR/sNKR-P1C expression by iNKT cells after stimulation with alpha-GalCer were examined. The s/cTCR(+ )s/cNKR-P1C(+) iNKT cells became undetectable after in vivo administration of alpha-GalCer, which was partially prevented by IL-12 neutralization. Whereas s/cNKR-P1C(+) iNKT cells became undetectable after in vivo administration of IL-12, s/cTCR(+) iNKT cells were only marginally affected. mRNA expression of TCR/NKR-P1C remained unaffected by alpha-GalCer or IL-12 treatment, despite the down-modulation of cTCR and/or cNKR-P1C protein expression. By contrast, cTCR(+ )cNKR-P1C(+) sTCR(-) sNKR-P1C(-) iNKT cells and cNKR-P1C(+) sNKR-P1C(-) iNKT cells were detectable after in vitro stimulation with alpha-GalCer and IL-12, respectively. Our results indicate that TCR and NKR-P1C expression by iNKT cells is differentially regulated by signalling through TCR and IL-12R. They also suggest that IL-12 participates, in part, in the disappearance of iNKT cells after stimulation with alpha-GalCer by down-modulating not only sNKR-P1C, but also sTCR.
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Affiliation(s)
- Masashi Emoto
- Laboratory of Immunology, Department of Laboratory Sciences, Gunma University School of Health Sciences, Maebashi, Gunma, Japan.
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36
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Gardner TR, Chen Q, Jin Y, Ajuebor MN. Toll-like receptor 3 ligand dampens liver inflammation by stimulating Valpha 14 invariant natural killer T cells to negatively regulate gammadeltaT cells. THE AMERICAN JOURNAL OF PATHOLOGY 2010; 176:1779-89. [PMID: 20167870 DOI: 10.2353/ajpath.2010.090738] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Valpha14 invariant natural killer T (Valpha14iNKT) cells are at the interface between the innate and adaptive immune responses and are thus critical for providing full engagement of host defense. We investigated the role of polyriboinosinic:polycytidylic acid (poly I:C), a replication-competent viral double-stranded RNA mimic and a specific agonist that recognizes the cellular sensor Toll-like receptor 3 (TLR3), in regulating Valpha14iNKT cell activation. We established for the first time that hepatic Valpha14iNKT cells up-regulate TLR3 extracellularly after poly I:C treatment. Notably, activation of TLR3-expressing hepatic Valpha14iNKT cells by a TLR3 ligand was suppressed by TLR3 deficiency. Our studies also revealed that Valpha14iNKT cell activation in response to poly I:C administration uniquely suppressed the accumulation and activation of intrahepatic gammadeltaT cells (but not natural killer cells) by inducing apoptosis. Furthermore, we established that activated hepatic Valpha14iNKT cells (via cytokines and possibly reactive oxygen species) influenced the frequency and absolute number of intrahepatic gammadeltaT cells, as evidenced by increased hepatic gammadeltaT cell accumulation in Valpha14iNKT cell-deficient mice after poly I:C treatment relative to wild-type mice. Thus, hepatic Valpha14iNKT cells and intrahepatic gammadeltaT cells are functionally linked on application of TLR3 agonist. Overall, our results demonstrate a novel and previously unrecognized anti-inflammatory role for activated hepatic Valpha14iNKT cells in negatively regulating intrahepatic gammadeltaT cell accumulation (probably through TLR3 signaling) and thereby preventing potentially harmful activation of intrahepatic gammadeltaT cells.
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Affiliation(s)
- Tommy R Gardner
- Department of Molecular & Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA
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Abstract
NKT cells are innate-like T lymphocytes that are found in rodents and primates. They are non-conventional T cells restricted by the CD1d molecule that presents self and exogenous glycolipids. NKT cells are unique in their ability to promptly secrete copious amounts of cytokines such as IFN-gamma and IL-4. Once activated, NKT cells can provide maturation signals to downstream cells, including DC, NK cells, and lymphocytes, thereby contributing to both innate and acquired immunity. Accordingly, NKT cells can influence a wide array of immune responses, including tumor surveillance, maintenance of self-tolerance and anti-infectious defenses. Studies performed with NKT-cell-deficient mice have shown that these cells are critical for the clearance of various pathogens. During bacterial infections, NKT cells can be activated either indirectly by DC or directly by bacterial lipid antigens presented by CD1d. Although viruses do not contain lipid antigens, NKT cells have also been implicated in antiviral responses. The capacity of NKT cells to regulate viral immune-surveillance, either constitutively or post-activation, makes them an attractive clinical target. In this review, we summarize recent publications dealing with the functions and relevance of NKT cells in the context of viral infections, both in murine models and in humans.
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Affiliation(s)
- Julien Diana
- INSERM, U561, Hôpital Cochin/St. Vincent de Paul, Université Paris Descartes, Paris, France
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38
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Gao B, Radaeva S, Park O. Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases. J Leukoc Biol 2009; 86:513-28. [PMID: 19542050 DOI: 10.1189/jlb.0309135] [Citation(s) in RCA: 293] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatic lymphocytes are enriched in NK and NKT cells that play important roles in antiviral and antitumor defenses and in the pathogenesis of chronic liver disease. In this review, we discuss the differential distribution of NK and NKT cells in mouse, rat, and human livers, the ultrastructural similarities and differences between liver NK and NKT cells, and the regulation of liver NK and NKT cells in a variety of murine liver injury models. We also summarize recent findings about the role of NK and NKT cells in liver injury, fibrosis, and repair. In general, NK and NKT cells accelerate liver injury by producing proinflammatory cytokines and killing hepatocytes. NK cells inhibit liver fibrosis via killing early-activated and senescent-activated stellate cells and producing IFN-gamma. In regulating liver fibrosis, NKT cells appear to be less important than NK cells as a result of hepatic NKT cell tolerance. NK cells inhibit liver regeneration by producing IFN-gamma and killing hepatocytes; however, the role of NK cells on the proliferation of liver progenitor cells and the role of NKT cells in liver regeneration have been controversial. The emerging roles of NK/NKT cells in chronic human liver disease will also be discussed.Understanding the role of NK and NKT cells in the pathogenesis of chronic liver disease may help us design better therapies to treat patients with this disease.
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Affiliation(s)
- Bin Gao
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, USA.
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Park O, Jeong WIL, Wang L, Wang H, Lian ZX, Gershwin ME, Gao B. Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride. Hepatology 2009; 49:1683-94. [PMID: 19205035 PMCID: PMC2772879 DOI: 10.1002/hep.22813] [Citation(s) in RCA: 154] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
UNLABELLED Liver fibrosis is a common scarring response to all forms of chronic liver injury and is always associated with inflammation that contributes to fibrogenesis. Although a variety of cell populations infiltrate the liver during inflammation, it is generically clear that CD8 T lymphocytes promote while natural killer (NK) cells inhibit liver fibrosis. However, the role of invariant natural killer T (iNKT) cells, which are abundant in the liver, in hepatic fibrogenesis, remains obscure. Here we show that iNKT-deficient mice are more susceptible to carbon tetrachloride (CCl(4))-induced acute liver injury and inflammation. The protective effect of naturally activated iNKT in this model is likely mediated via suppression of the proinflammatory effect of activated hepatic stellate cells. Interestingly, strong activation of iNKT through injection of iNKT activator alpha-galactosylceramide (alpha-GalCer) accelerates CCl(4)-induced acute liver injury and fibrosis. In contrast, chronic CCl(4) administration induces a similar degree of liver injury in iNKT-deficient and wild-type mice, and only a slightly higher grade of liver fibrosis in iNKT-deficient mice than wild-type mice 2 weeks but not 4 weeks after CCl(4) injection, although iNKT cells are able to kill activated stellate cells. An insignificant role of iNKT in chronic liver injury and fibrosis may be attributable to hepatic iNKT cell depletion. Finally, chronic alpha-GalCer treatment had little effect on liver injury and fibrosis, which is attributable to iNKT tolerance after alpha-GalCer injection. CONCLUSION Natural activation of hepatic iNKT cells inhibits, whereas strong activation of iNKT cells by alpha-GalCer accelerates CCl(4)-induced acute liver injury, inflammation, and fibrosis. During chronic liver injury, hepatic iNKT cells are depleted and play a role in inhibiting liver fibrosis in the early stage but not the late stage of fibrosis.
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Affiliation(s)
- Ogyi Park
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Won-IL Jeong
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Lei Wang
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Hua Wang
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Zhe-Xiong Lian
- Division of Rheumatology, University of California at Davis, Davis, CA 95616, USA
| | - M. Eric Gershwin
- Division of Rheumatology, University of California at Davis, Davis, CA 95616, USA
| | - Bin Gao
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
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Tessmer MS, Fatima A, Paget C, Trottein F, Brossay L. NKT cell immune responses to viral infection. Expert Opin Ther Targets 2009; 13:153-62. [PMID: 19236234 DOI: 10.1517/14712590802653601] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Natural killer T (NKT) cells are a heterogeneous population of innate T cells that have attracted interest because of their potential to regulate immune responses to a variety of pathogens. The most widely studied NKT cell subset is the invariant (i)NKT cells that recognize glycolipids in the context of the CD1d molecule. The multifaceted methods of activation iNKT cells possess and their ability to produce regulatory cytokines has made them a primary target for studies. OBJECTIVE/METHODS To give insights into the roles of iNKT cells during infectious diseases, particularly viral infections. We also highlight mechanisms leading to iNKT cell activation in response to pathogens. CONCLUSIONS iNKT cell's versatility allows them to detect and respond to several viruses. Therapeutic approaches to specifically target iNKT cells will require additional research. Notably, the roles of non-invariant NKT cells in response to pathogens warrant further investigation.
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Affiliation(s)
- Marlowe S Tessmer
- Brown University, Department of Molecular Microbiology and Immunology, Providence, USA
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X-linked lymphoproliferative disease (XLP): a model of impaired anti-viral, anti-tumor and humoral immune responses. Immunol Res 2009; 42:145-59. [PMID: 18815745 DOI: 10.1007/s12026-008-8048-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
A major focus of our research is to understand the molecular and cellular basis of X-linked lymphoproliferative disease (XLP), a rare and often fatal immunodeficiency caused by mutations in the SH2D1A gene, which encodes the adaptor molecule SAP. Recently, we observed that SAP is essential for the development of natural killer T (NKT) cells, a lymphocyte population that participates in protection against certain tumors, infections, and autoimmune states. In this review, we describe the approaches that we are taking to understand the role of SAP in immune cells, including NKT cells. By using SAP as the focal point of our studies, we hope to identify novel signaling pathways that could be targeted to improve the treatment for patients with XLP as well as more common disorders, such as autoimmunity and cancer.
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Abstract
The invariant (i) natural killer (NK)T cells represent a unique subset of T lymphocytes which express the V alpha 14 chain of the T cell receptor (TCR), that recognizes glycolipid antigens presented by the nonpolymorphic major histocompatibility complex (MHC) class I-like antigen presentation molecule CD1d, and they participate in protection against some microbial pathogens. Although iNKT cells have originally been regarded as T cells co-expressing NKR-P1B/C (NK1.1: CD 161), they do not seem to consistently express this marker, since NK1.1 surface expression on iNKT cells undergoes dramatic changes following facultative intracellular bacterial infection, which is correlated with functional changes of this cell population. Accumulating evidence suggests that NK1.1 allows recognition of "missing-self", thus controlling activation/inhibition of NK1.1-expressing cells. Therefore, it is tempting to suggest that iNKT cells participate in the regulation of host immune responses during facultative intracellular bacterial infection by controlling NK1.1 surface expression. These findings shed light not only on the unique role of iNKT cells in microbial infection, but also provide evidence for new aspects of the NK1.1 as a regulatory molecule on these cells.
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Affiliation(s)
- Masashi Emoto
- Laboratory of Immunology, Department of Laboratory Sciences, Gunma University School of Health Sciences, Maebashi, Gunma, Japan.
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43
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Diana J, Griseri T, Lagaye S, Beaudoin L, Autrusseau E, Gautron AS, Tomkiewicz C, Herbelin A, Barouki R, von Herrath M, Dalod M, Lehuen A. NKT cell-plasmacytoid dendritic cell cooperation via OX40 controls viral infection in a tissue-specific manner. Immunity 2009; 30:289-99. [PMID: 19217323 DOI: 10.1016/j.immuni.2008.12.017] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2007] [Revised: 11/14/2008] [Accepted: 12/19/2008] [Indexed: 11/25/2022]
Abstract
Invariant natural killer T (iNKT) cells promote immune responses to various pathogens, but exactly how iNKT cells control antiviral responses is unclear. Here, we showed that iNKT cells induced tissue-specific antiviral effects in mice infected by lymphocytic choriomeningitis virus (LCMV). Indeed, iNKT cells inhibited viral replication in the pancreas and liver but not in the spleen. In the pancreas, iNKT cells expressed the OX40 molecule and promoted type I interferon (IFN) production by plasmacytoid dendritic cells (pDCs) through OX40-OX40 ligand interaction. Subsequently, this iNKT cell-pDC cooperation attenuated the antiviral adaptive immune response in the pancreas but not in the spleen. The dampening of pancreatic anti-LCMV CD8(+) T cell response prevented tissue damage in transgenic mice expressing LCMV protein in islet beta cells. Thus, this study identifies pDCs as an essential partner of iNKT cells for mounting an efficient, nondeleterious antiviral response in peripheral tissue.
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Affiliation(s)
- Julien Diana
- Institut National de la Santé et de la Recherche Médicale U561, Hôpital Cochin-St Vincent de Paul, Paris, France
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Guy CS, Mulrooney-Cousins PM, Churchill ND, Michalak TI. Intrahepatic expression of genes affiliated with innate and adaptive immune responses immediately after invasion and during acute infection with woodchuck hepadnavirus. J Virol 2008; 82:8579-91. [PMID: 18596101 PMCID: PMC2519695 DOI: 10.1128/jvi.01022-08] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2008] [Accepted: 06/23/2008] [Indexed: 02/07/2023] Open
Abstract
The importance of effective immune responses in recovery from acute hepadnaviral hepatitis has been demonstrated. However, there is no conclusive delineation of virological and immunological events occurring in the liver immediately after hepadnavirus invasion and during the preacute phase of infection. These very early events might be of primary importance in determining the recovery or progression to chronic hepatitis and the intrinsic hepadnaviral propensity to persist. In this study, applying the woodchuck model of acute hepatitis B, the hepatic kinetics of hepadnavirus replication and activation of genes encoding cytokines, cytotoxicity effectors, and immune cell markers were quantified in sequential liver biopsies collected from 1 h postinoculation onward by sensitive real-time cDNA amplification assays. The results revealed that hepadnavirus replication is established in the liver as early as 1 hour after infection. In 3 to 6 h, significantly augmented intrahepatic transcription of gamma interferon and interleukin-12 were evident, suggesting activation of antigen-presenting cells. In 48 to 72 h, NK and NKT cells were activated and virus replication was transiently but significantly reduced, implying that this early innate response is at least partially successful in limiting virus propagation. Nonetheless, T cells were activated 4 to 5 weeks later when hepatitis became histologically evident. Collectively, our data demonstrate that virus replication is initiated and the innate response activated in the liver soon after exposure to a liver-pathogenic dose of hepadnavirus. Nevertheless, this response is unable to prompt a timely adaptive T-cell response, in contrast to infections caused by other viral pathogens.
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Affiliation(s)
- Clifford S Guy
- Division of BioMedical Science, Molecular Virology and Hepatology Research Group, Discipline of Laboratory Medicine, Faculty of Medicine, Health Science Centre, Memorial University, St John's, Newfoundland, Canada
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Chiba A, Dascher CC, Besra GS, Brenner MB. Rapid NKT Cell Responses Are Self-Terminating during the Course of Microbial Infection. THE JOURNAL OF IMMUNOLOGY 2008; 181:2292-302. [DOI: 10.4049/jimmunol.181.4.2292] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Wesley JD, Tessmer MS, Chaukos D, Brossay L. NK cell-like behavior of Valpha14i NK T cells during MCMV infection. PLoS Pathog 2008; 4:e1000106. [PMID: 18636102 PMCID: PMC2442879 DOI: 10.1371/journal.ppat.1000106] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2008] [Accepted: 06/19/2008] [Indexed: 01/12/2023] Open
Abstract
Immunity to the murine cytomegalovirus (MCMV) is critically dependent on the innate response for initial containment of viral replication, resolution of active infection, and proper induction of the adaptive phase of the anti-viral response. In contrast to NK cells, the Valpha14 invariant natural killer T cell response to MCMV has not been examined. We found that Valpha14i NK T cells become activated and produce significant levels of IFN-gamma, but do not proliferate or produce IL-4 following MCMV infection. In vivo treatment with an anti-CD1d mAb and adoptive transfer of Valpha14i NK T cells into MCMV-infected CD1d(-/-) mice demonstrate that CD1d is dispensable for Valpha14i NK T cell activation. In contrast, both IFN-alpha/beta and IL-12 are required for optimal activation. Valpha14i NK T cell-derived IFN-gamma is partially dependent on IFN-alpha/beta but highly dependent on IL-12. Valpha14i NK T cells contribute to the immune response to MCMV and amplify NK cell-derived IFN-gamma. Importantly, mortality is increased in CD1d(-/-) mice in response to high dose MCMV infection when compared to heterozygote littermate controls. Collectively, these findings illustrate the plasticity of Valpha14i NK T cells that act as effector T cells during bacterial infection, but have NK cell-like behavior during the innate immune response to MCMV infection.
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Affiliation(s)
- Johnna D. Wesley
- Department of Molecular Microbiology and Immunology and Graduate Program in Pathobiology, Division of Biology and Medicine, Brown University, Providence, Rhode Island, United States of America
| | - Marlowe S. Tessmer
- Department of Molecular Microbiology and Immunology and Graduate Program in Pathobiology, Division of Biology and Medicine, Brown University, Providence, Rhode Island, United States of America
| | - Deanna Chaukos
- Department of Molecular Microbiology and Immunology and Graduate Program in Pathobiology, Division of Biology and Medicine, Brown University, Providence, Rhode Island, United States of America
| | - Laurent Brossay
- Department of Molecular Microbiology and Immunology and Graduate Program in Pathobiology, Division of Biology and Medicine, Brown University, Providence, Rhode Island, United States of America
- * E-mail:
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Type I NKT cells protect (and type II NKT cells suppress) the host's innate antitumor immune response to a B-cell lymphoma. Blood 2008; 111:5637-45. [PMID: 18417738 DOI: 10.1182/blood-2007-05-092866] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Natural killer T (NKT) cells are a T-cell subpopulation known to possess immunoregulatory functions and recognize CD1d molecules. The majority of NKT cells express an invariant T-cell receptor (TCR) alpha chain rearrangement (Valpha14 Jalpha18 in mice; Valpha24 Jalpha18 in humans) and are called type I NKT cells; all other NKT cells are type II. In the current study, we have analyzed the roles for these NKT-cell subsets in the host's innate antitumor response against a murine B-cell lymphoma model in vivo. In tumor-bearing mice, we found that type I NKT cells conferred protection in a CD1d-dependent manner, whereas type II NKT cells exhibited inhibitory activity. Pro- and anti-inflammatory cytokines secreted by splenocytes from tumor-bearing mice correlated with tumor progression. Myeloid cells (CD11b(+)Gr1(+)) were present in large numbers at the tumor site and in the spleen of tumor-bearing type I NKT-deficient mice, suggesting that antitumor immunosurveillance was inhibited by CD11b(+)Gr1(+) cells. Overall, these data suggest that there are distinct roles for NKT-cell subsets in response to a B-cell lymphoma in vivo, pointing to potential novel targets to be exploited in immunotherapeutic approaches against blood cancers.
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Role of interleukin-12 in determining differential kinetics of invariant natural killer T cells in response to differential burden of Listeria monocytogenes. Microbes Infect 2007; 10:224-32. [PMID: 18321748 DOI: 10.1016/j.micinf.2007.11.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2007] [Revised: 10/31/2007] [Accepted: 11/21/2007] [Indexed: 11/24/2022]
Abstract
Invariant (i) natural killer (NK) T cells are unique T lymphocytes expressing NKR-P1B/C (NK1.1), which recognize glycolipids, notably alpha-galactosylceramide (alpha-GalCer) presented by CD1d. The characteristic phenotype of these iNKT cells undergoes dramatic changes following Listeria monocytogenes infection, and interleukin (IL)-12 is involved in these alterations. Here we show that liver iNKT cells in mice are differentially influenced by the load of infection. Liver alpha-GalCer/CD1d tetramer-reactive (alpha-GalCer/CD1d(+)) T cells expressing NK1.1 became undetectable by day 2 following L. monocytogenes infection and concomitantly cells lacking NK1.1 increased regardless of the severity of infection. Whereas alpha-GalCer/CD1d(+)NK1.1(+) T cells remained virtually undetectable on day 4 following low-dose infection, considerable numbers of these cells were detected in high-dose-infected mice. Whereas numbers of IL-12 producers in the liver on day 4 post infection were comparable in low- and high-dose-infected mice without in vitro restimulation with heat-killed Listeria, those were more prominent in low-dose-infected mice than in high-dose-infected mice after restimulation despite the fact that higher numbers of macrophages and granulocytes infiltrated the liver in high-dose-infected mice than in low-dose-infected mice. Our results indicate that NK1.1 surface expression on iNKT cells is differentially modulated by the burden of infection, and suggest that a high bacterial load probably causes loss of IL-12 production.
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c-Jun NH2-terminal kinase 2 inhibits gamma interferon production during Anaplasma phagocytophilum infection. Infect Immun 2007; 76:308-16. [PMID: 17998313 DOI: 10.1128/iai.00599-07] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Gamma interferon (IFN-gamma) plays a critical role in the early eradication of Anaplasma phagocytophilum. However, the mechanisms that regulate IFN-gamma production upon infection remain poorly understood. Here we show that c-Jun NH2-terminal kinase 2 (JNK2) inhibits IFN-gamma production during A. phagocytophilum infection. jnk2-null mice were more refractory to infection with A. phagocytophilum and produced increased levels of IFN-gamma after challenge with the pathogen. The resistance of jnk2-null mice to A. phagocytophilum infection was due to elevated levels of IFN-gamma secreted by conventional and natural killer (NK) T cells. The administration of alpha-galactosylceramide, a strong NK T-cell agonist, increased IFN-gamma release and protected mice from A. phagocytophilum, further demonstrating the inhibitory effect of JNK2 on IFN-gamma production. Collectively, these findings provide strong evidence that JNK2 is an important regulatory protein for IFN-gamma secretion upon challenge with A. phagocytophilum.
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Emoto M, Yoshizawa I, Emoto Y, Takahashi Y, Hurwitz R, Miamoto M, Kaufmann SH. Reversible NK1.1 surface expression on invariant liver natural killer T cells during Listeria monocytogenes infection. Microbes Infect 2007; 9:1511-20. [DOI: 10.1016/j.micinf.2007.09.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2007] [Revised: 08/23/2007] [Accepted: 09/26/2007] [Indexed: 11/28/2022]
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