|
1
|
Zhu YJ, Zhang Y, Rao Y, Jiang Y, Liu YG, Li JZ, Yuan JQ, Zhao Y, Zheng WW, Ma L, Wang CY, Li J. Evaluation of autoimmune phenomena in patients with nonalcoholic fatty liver disease on the basis of liver pathology. World J Hepatol 2024; 16:1407-1416. [DOI: 10.4254/wjh.v16.i12.1407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 10/14/2024] [Accepted: 10/29/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Autoimmune phenomena can be used in some patients with nonalcoholic fatty liver disease (NAFLD) in the clinic, but these patients are not autoimmune hepatitis patients.
AIM To determine whether autoimmunity is present in patients with NAFLD, this study was performed.
METHODS A total of 104 patients with NAFLD diagnosed by liver biopsy at Tianjin Second People’s Hospital between 2019 and 2023 were enrolled. The patients were divided into three groups according to their biopsy results: The NAFL (n = 36), nonalcoholic steatohepatitis (n = 51), and liver cirrhosis groups (n = 17).
RESULTS The differences in IgA, an immune marker, among the three groups of patients were statistically significant (P = 0.025). In all NAFLD patients, antinuclear antibody and anti-smooth muscle antibody were the most common autoantibodies. The antinuclear antibody detection rate was the highest at 48.1%. The cirrhosis group had the highest autoantibody positivity rate (64.7%). Portal enlargement is also common in NAFLD patients. The rates of positivity for portal lymphoplasmacytic infiltration, small bile duct hyperplasia and interfacial hepatitis were highest in the cirrhosis group; the differences between the cirrhosis group and the other two groups were significant (P < 0.05). Hepatocellular rosettes were identified only in the cirrhosis group (11.8%).
CONCLUSION Autoimmune phenomena occur in NAFLD patients, especially in patients with NAFLD-related cirrhosis, in whom this phenomenon may be more pronounced.
Collapse
Affiliation(s)
- Yu-Jin Zhu
- Department of Infectious Diseases, Xi’an No. 3 Hospital, the Affiliated Hospital of Northwest University, Xi’an 710018, Shaanxi Province, China
| | - Yan Zhang
- Department of Epidemiology, Tianjin Medical University, Tianjin 300070, China
| | - Yao Rao
- Department of Gastroenterology, Clinical School of the Second People's Hospital, Tianjin 300110, China
| | - Yong Jiang
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Yong-Gang Liu
- Department of Pathology, Clinical School of the Second People's Hospital, Tianjin 300110, China
| | - Jian-Zhou Li
- Department of Gastro-Enterologie, Xining Second People's Hospital, Xining 810003, Qinghai Province, China
| | - Jia-Qi Yuan
- Department of Gastro-Enterologie, Xining Second People's Hospital, Xining 810003, Qinghai Province, China
| | - Ying Zhao
- Department of Epidemiology, Tianjin Medical University, Tianjin 300070, China
| | - Wen-Wen Zheng
- Department of Epidemiology, Tianjin Medical University, Tianjin 300070, China
| | - Lin Ma
- Department of Epidemiology, Tianjin Medical University, Tianjin 300070, China
| | - Chun-Yan Wang
- Department of Gastroenterology, Clinical School of the Second People's Hospital, Tianjin 300110, China
| | - Jia Li
- Department of Gastroenterology, Clinical School of the Second People's Hospital, Tianjin 300110, China
| |
Collapse
|
|
2
|
Rajashekar V, Stern L, Almeida CF, Slobedman B, Abendroth A. The surveillance of viral infections by the unconventional Type I NKT cell. Front Immunol 2024; 15:1472854. [PMID: 39355244 PMCID: PMC11442276 DOI: 10.3389/fimmu.2024.1472854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 08/26/2024] [Indexed: 10/03/2024] Open
Abstract
Type I NKT cells, also known as Invariant Natural Killer T (iNKT) cells, are a subpopulation of unconventional, innate-like T (ILT) cells which can proficiently influence downstream immune effector functions. Type I NKT cells express a semi-invariant αβ T cell receptor (TCR) that recognises lipid-based ligands specifically presented by the non-classical cluster of differentiation (CD1) protein d (CD1d) molecule. Due to their potent immunomodulatory functional capacity, type I NKT cells are being increasingly considered in prophylactic and therapeutic approaches towards various diseases, including as vaccine-adjuvants. As viruses do not encode lipid synthesis, it is surprising that many studies have shown that some viruses can directly impede type I NKT activation through downregulating CD1d expression. Therefore, in order to harness type I NKT cells for potential anti-viral therapeutic uses, it is critical that we fully appreciate how the CD1d-iNKT cell axis interacts with viral immunity. In this review, we examine clinical findings that underpin the importance of type I NKT cell function in viral infections. This review also explores how certain viruses employ immunoevasive mechanisms and directly encode functions to target CD1d expression and type I NKT cell function. Overall, we suggest that the CD1d-iNKT cell axis may hold greater gravity within viral infections than what was previously appreciated.
Collapse
Affiliation(s)
- Varshini Rajashekar
- Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
- Sydney Institute for Infectious Diseases , University of Sydney, Sydney, NSW, Australia
| | - Lauren Stern
- Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
- Sydney Institute for Infectious Diseases , University of Sydney, Sydney, NSW, Australia
| | - Catarina F. Almeida
- Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Barry Slobedman
- Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
- Sydney Institute for Infectious Diseases , University of Sydney, Sydney, NSW, Australia
| | - Allison Abendroth
- Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
- Sydney Institute for Infectious Diseases , University of Sydney, Sydney, NSW, Australia
| |
Collapse
|
|
3
|
Zhao W, Li M, Song S, Zhi Y, Huan C, Lv G. The role of natural killer T cells in liver transplantation. Front Cell Dev Biol 2024; 11:1274361. [PMID: 38250325 PMCID: PMC10796773 DOI: 10.3389/fcell.2023.1274361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 12/15/2023] [Indexed: 01/23/2024] Open
Abstract
Natural killer T cells (NKTs) are innate-like lymphocytes that are abundant in the liver and participate in liver immunity. NKT cells express both NK cell and T cell markers, modulate innate and adaptive immune responses. Type I and Type II NKT cells are classified according to the TCR usage, while they recognize lipid antigen in a non-classical major histocompatibility (MHC) molecule CD1d-restricted manner. Once activated, NKT cells can quickly produce cytokines and chemokines to negatively or positively regulate the immune responses, depending on the different NKT subsets. In liver transplantation (LTx), the immune reactions in a series of processes determine the recipients' long-term survival, including ischemia-reperfusion injury, alloresponse, and post-transplant infection. This review provides insight into the research on NKT cells subpopulations in LTx immunity during different processes, and discusses the shortcomings of the current research on NKT cells. Additionally, the CD56-expressing T cells are recognized as a NK-like T cell population, they were also discussed during these processes.
Collapse
Affiliation(s)
- Wenchao Zhao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Mingqian Li
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Shifei Song
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yao Zhi
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Chen Huan
- Center of Infectious Diseases and Pathogen Biology, Institute of Virology and AIDS Research, Key Laboratory of Organ Regeneration and Transplantation of The Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Guoyue Lv
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| |
Collapse
|
|
4
|
Zheng S, Yang W, Yao D, Tang S, Hou J, Chang X. A comparative study on roles of natural killer T cells in two diet-induced non-alcoholic steatohepatitis-related fibrosis in mice. Ann Med 2022; 54:2233-2245. [PMID: 35950602 PMCID: PMC9377241 DOI: 10.1080/07853890.2022.2108894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Immune responses are important in the progression of non-alcoholic fatty liver disease (NAFLD). Natural killer T (NKT) cells are main components of the innate immune system that modulate immunity. However, the role of NKT cells in NAFLD remains controversial. OBJECTIVE We aimed to investigate the role of NKT cells in non-alcoholic steatohepatitis (NASH)-related fibrosis in fast food diet (FFD)- and methionine choline-deficient (MCD) diet-induced mouse models. METHODS Hepatic NKT cells were analysed in wild-type (WT) and CD1d-/- mice fed FFD or MCD diets. Hepatic pathology, cytokine profiles and liver fibrosis were evaluated. Furthermore, the effect of chronic administration of α-galactosylceramide (α-GalCer) on liver fibrosis was investigated in both FFD- and MCD-treated mice. RESULTS FFD induced a significant depletion of hepatic NKT cells, thus leading to mild to moderate NASH and early-stage fibrosis, while mice fed MCD diets developed severe liver inflammation and progressive fibrosis without a significant change in hepatic NKT cell abundance. FFD induced a similar liver fibrogenic response in CD1d-/- and WT mice, while MCD induced a higher hepatic mRNA expression of Col1α1 and TIMP1 as well as relative fibrosis density in CD1d-/- mice than WT mice (31.8 vs. 16.3, p = .039; 40.0 vs. 22.6, p = .019; 2.24 vs. 1.59, p = .036). Chronic administration of α-GalCer induced a higher hepatic mRNA expression of TIMP1 in MCD-treated mice than controls (36.7 vs. 14.9, p = .005). CONCLUSION NKT cells have protective roles in NAFLD as the disease progresses. During diet-induced steatosis, mild to moderate NASH and the early stage of fibrosis, hepatic NKT cells are relatively depleted, leading to a proinflammatory status. In severe NASH and the advanced stage of liver fibrosis, NKT cells play a role in inhibiting the NASH-related fibrogenic response. Chronic administration of α-GalCer induces NKT cell anergy and tolerance, which may play a role in promoting the liver fibrogenic response.
Collapse
Affiliation(s)
- Shumei Zheng
- Department of Gastroenterology and Hepatology, The General Hospital of Western Theater Command, Chengdu, China
| | - Wenzhuo Yang
- Department of Gastroenterology and Hepatology, Shanghai Tongji Hospital, Shanghai Tongji University, Shanghai, China
| | - Dongmei Yao
- Department of Gastroenterology and Hepatology, the Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Shanhong Tang
- Department of Gastroenterology and Hepatology, The General Hospital of Western Theater Command, Chengdu, China
| | - Juanni Hou
- Department of Gastroenterology and Hepatology, The General Hospital of Western Theater Command, Chengdu, China
| | - Xing Chang
- Department of Gastroenterology and Hepatology, The General Hospital of Western Theater Command, Chengdu, China
| |
Collapse
|
|
5
|
Gu X, Chu Q, Ma X, Wang J, Chen C, Guan J, Ren Y, Wu S, Zhu H. New insights into iNKT cells and their roles in liver diseases. Front Immunol 2022; 13:1035950. [PMID: 36389715 PMCID: PMC9643775 DOI: 10.3389/fimmu.2022.1035950] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 10/14/2022] [Indexed: 08/29/2023] Open
Abstract
Natural killer T cells (NKTs) are an important part of the immune system. Since their discovery in the 1990s, researchers have gained deeper insights into the physiology and functions of these cells in many liver diseases. NKT cells are divided into two subsets, type I and type II. Type I NKT cells are also named iNKT cells as they express a semi-invariant T cell-receptor (TCR) α chain. As part of the innate immune system, hepatic iNKT cells interact with hepatocytes, macrophages (Kupffer cells), T cells, and dendritic cells through direct cell-to-cell contact and cytokine secretion, bridging the innate and adaptive immune systems. A better understanding of hepatic iNKT cells is necessary for finding new methods of treating liver disease including autoimmune liver diseases, alcoholic liver diseases (ALDs), non-alcoholic fatty liver diseases (NAFLDs), and liver tumors. Here we summarize how iNKT cells are activated, how they interact with other cells, and how they function in the presence of liver disease.
Collapse
Affiliation(s)
- Xinyu Gu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiao Ma
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jing Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chao Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Guan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yanli Ren
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shanshan Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haihong Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| |
Collapse
|
|
6
|
NKT cells adopt a glutamine-addicted phenotype to regulate their homeostasis and function. Cell Rep 2022; 41:111516. [DOI: 10.1016/j.celrep.2022.111516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 05/19/2022] [Accepted: 09/26/2022] [Indexed: 11/20/2022] Open
|
|
7
|
Prevalence and Significance of Antinuclear Antibodies in Biopsy-Proven Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. DISEASE MARKERS 2022; 2022:8446170. [PMID: 35990246 PMCID: PMC9391168 DOI: 10.1155/2022/8446170] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/06/2022] [Accepted: 06/30/2022] [Indexed: 12/27/2022]
Abstract
Aim Associations between antinuclear antibodies (ANAs) and disease severity in nonalcoholic fatty liver disease (NAFLD) remain unclear. This study aimed to provide reliable estimates of ANA prevalence in subjects with biopsy-proven NAFLD and to investigate whether its associations with liver disease severity were established. Methods Observational studies measuring ANA in NAFLD patients were derived from the PubMed, Embase, and Web of Science databases from inception to March 30, 2022. The effect size was presented as the pooled risk difference, unstandardized mean differences (MDs), and odds ratio (OR) with a 95% confidence interval (CI). Results Thirteen articles involving 2331 patients were finally included. Among the subjects with biopsy-proven NAFLD, the overall prevalence of ANA positivity was high as 23% (95% CI: 19%-28%), but there were no statistically significant differences between ANA-positive and ANA-negative NAFLD patients in the levels of liver enzymes and blood lipids, grades of hepatocellular ballooning, lobular and portal inflammation, or risks of moderate-severe steatosis and significant fibrosis. However, the subgroup analysis showed that different geographic regions led to diverse results. ANA positivity was associated with a significantly elevated risk of significant fibrosis in the Eastern population (OR = 2.30, 95% CI: 1.30-4.06) but not in the Western population (OR = 1.00, 95% CI: 0.54-1.83). Conclusions Serum ANA was present in approximately one-quarter of subjects with biopsy-proven NAFLD, but it conferred a greater risk of significant fibrosis only in Eastern but not Western populations.
Collapse
|
|
8
|
Senff T, Menne C, Cosmovici C, Lewis-Ximenez LL, Aneja J, Broering R, Kim AY, Westendorf AM, Dittmer U, Scherbaum N, Lauer GM, Timm J. Peripheral blood iNKT cell activation correlates with liver damage during acute hepatitis C. JCI Insight 2021; 7:155432. [PMID: 34905514 PMCID: PMC8855829 DOI: 10.1172/jci.insight.155432] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/08/2021] [Indexed: 11/17/2022] Open
Abstract
Invariant NK T (iNKT) cells are implicated in viral clearance; however, their role in hepatitis C virus (HCV) infection remains controversial. Here, iNKT cells were studied during different stages of HCV infection. iNKT cells from patients with acute HCV infection and people who inject drugs (PWID) with chronic or spontaneously resolved HCV infection were characterized by flow cytometry. In a longitudinal analysis during acute HCV infection, frequencies of activated CD38+ iNKT cells reproducibly declined in spontaneously resolving patients, whereas they were persistently elevated in patients progressing to chronic infection. During the first year of infection, the frequency of activated CD38+ or CD69+ iNKT cells strongly correlated with alanine transaminase levels with particularly pronounced correlations in spontaneously resolving patients. Increased frequencies of activated iNKT cells in chronic HCV infection were confirmed in cross-sectional analyses of PWID with chronic or spontaneously resolved HCV infection; however, no apparent functional differences were observed with various stimulation protocols. Our data suggest that iNKT cells are activated during acute hepatitis C and that activation is sustained in chronic infection. The correlation between the frequency of activated iNKT cells and alanine transaminase may point toward a role of iNKT cells in liver damage.
Collapse
Affiliation(s)
- Tina Senff
- Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Christopher Menne
- Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Christine Cosmovici
- Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | | | - Jasneet Aneja
- Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
| | - Ruth Broering
- Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany
| | - Arthur Y Kim
- Department of Medicine, Massachusetts General Hospital, Boston, United States of America
| | - Astrid M Westendorf
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Ulf Dittmer
- Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Norbert Scherbaum
- Department for Addiction Medicine and Addictive Behavior, LVR-Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Georg M Lauer
- Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
| | - Jörg Timm
- Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| |
Collapse
|
|
9
|
Vogt S, Mattner J. NKT Cells Contribute to the Control of Microbial Infections. Front Cell Infect Microbiol 2021; 11:718350. [PMID: 34595131 PMCID: PMC8477047 DOI: 10.3389/fcimb.2021.718350] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/25/2021] [Indexed: 12/14/2022] Open
Abstract
Innate (-like) T lymphocytes such as natural killer T (NKT) cells play a pivotal role in the recognition of microbial infections and their subsequent elimination. They frequently localize to potential sites of pathogen entry at which they survey extracellular and intracellular tissue spaces for microbial antigens. Engagement of their T cell receptors (TCRs) induces an explosive release of different cytokines and chemokines, which often pre-exist as constitutively expressed gene transcripts in NKT cells and underlie their poised effector state. Thus, NKT cells regulate immune cell migration and activation and subsequently, bridge innate and adaptive immune responses. In contrast to conventional T cells, which react to peptide antigens, NKT cells recognize lipids presented by the MHC class I like CD1d molecule on antigen presenting cells (APCs). Furthermore, each NKT cell TCR can recognize various antigen specificities, whereas a conventional T lymphocyte TCR reacts mostly only to one single antigen. These lipid antigens are either intermediates of the intracellular APC`s-own metabolism or originate from the cell wall of different bacteria, fungi or protozoan parasites. The best-characterized subset, the type 1 NKT cell subset expresses a semi-invariant TCR. In contrast, the TCR repertoire of type 2 NKT cells is diverse. Furthermore, NKT cells express a panoply of inhibitory and activating NK cell receptors (NKRs) that contribute to their primarily TCR-mediated rapid, innate like immune activation and even allow an adaption of their immune response in an adoptive like manner. Dueto their primary localization at host-environment interfaces, NKT cells are one of the first immune cells that interact with signals from different microbial pathogens. Vice versa, the mutual exchange with local commensal microbiota shapes also the biology of NKT cells, predominantly in the gastrointestinal tract. Following infection, two main signals drive the activation of NKT cells: first, cognate activation upon TCR ligation by microbial or endogenous lipid antigens; and second, bystander activation due to cytokines. Here we will discuss the role of NKT cells in the control of different microbial infections comparing pathogens expressing lipid ligands in their cell walls to infectious agents inducing endogenous lipid antigen presentation by APCs.
Collapse
Affiliation(s)
- Stefan Vogt
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Jochen Mattner
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany
| |
Collapse
|
|
10
|
Carranza-Trejo AM, Vetvicka V, Vistejnova L, Kralickova M, Montufar EB. Hepatocyte and immune cell crosstalk in non-alcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2021; 15:783-796. [PMID: 33557653 DOI: 10.1080/17474124.2021.1887730] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: Nonalcoholic fatty liver disease (NAFLD) is the most widespread chronic liver disease in the world. It can evolve into nonalcoholic steatohepatitis (NASH) where inflammation and hepatocyte ballooning are key participants in the determination of this steatotic state.Areas covered: To provide a systematic overview and current understanding of the role of inflammation in NAFLD and its progression to NASH, the function of the cells involved, and the activation pathways of the innate immunity and cell death; resulting in inflammation and chronic liver disease. A PubMed search was made with relevant articles together with relevant references were included for the writing of this review.Expert opinion: Innate and adaptive immunity are the key players in the NAFLD progression; some of the markers presented during NAFLD are also known to be immunity biomarkers. All cells involved in NAFLD and NASH are known to have immunoregulatory properties and their imbalance will completely change the cytokine profile and form a pro-inflammatory microenvironment. It is necessary to fully answer the question of what initiators and metabolic imbalances are particularly important, considering sterile inflammation as the architect of the disease. Due to the shortage of elucidation of NASH progression, we discuss in this review, how inflammation is a key part of this development and we presume the targets should lead to inflammation and oxidative stress treatment.
Collapse
Affiliation(s)
| | - Vaclav Vetvicka
- Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, KY, USA
| | - Lucie Vistejnova
- Biomedical Centre, Medical Faculty in Pilsen, Charles University, Pilsen, Czech Republic
| | - Milena Kralickova
- Biomedical Centre, Medical Faculty in Pilsen, Charles University, Pilsen, Czech Republic
| | - Edgar B Montufar
- Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic
| |
Collapse
|
|
11
|
Heinrichs D, Brandt EF, Fischer P, Köhncke J, Wirtz TH, Guldiken N, Djudjaj S, Boor P, Kroy D, Weiskirchen R, Bucala R, Wasmuth HE, Strnad P, Trautwein C, Bernhagen J, Berres ML. Unexpected Pro-Fibrotic Effect of MIF in Non-Alcoholic Steatohepatitis Is Linked to a Shift in NKT Cell Populations. Cells 2021; 10:252. [PMID: 33525493 PMCID: PMC7918903 DOI: 10.3390/cells10020252] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/20/2021] [Accepted: 01/22/2021] [Indexed: 12/29/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine with anti-fibrotic properties in toxic liver injury models and anti-steatotic functions in non-alcoholic fatty liver disease (NAFLD) attributed to the CD74/AMPK signaling pathway. As NAFLD progression is associated with fibrosis, we studied MIF function during NAFLD-associated liver fibrogenesis in mice and men by molecular, histological and immunological methods in vitro and in vivo. After NASH diet feeding, hepatic Mif expression was strongly induced, an effect which was absent in Mif∆hep mice. In contrast to hepatotoxic fibrosis models, NASH diet-induced fibrogenesis was significantly abrogated in Mif-/- and Mif∆hep mice associated with a reduced accumulation of the pro-fibrotic type-I NKT cell subpopulation. In vitro, MIF skewed the differentiation of NKT cells towards the type-I subtype. In line with the murine results, expression of fibrosis markers strongly correlated with MIF, its receptors, and markers of NKT type-I cells in NASH patients. We conclude that MIF expression is induced during chronic metabolic injury in mice and men with hepatocytes representing the major source. In NAFLD progression, MIF contributes to liver fibrogenesis skewing NKT cell polarization toward a pro-fibrotic phenotype highlighting the complex, context-dependent role of MIF during chronic liver injury.
Collapse
Affiliation(s)
- Daniel Heinrichs
- Department of Internal Medicine III, RWTH Aachen University, 52074 Aachen, Germany; (D.H.); (E.F.B.); (P.F.); (J.K.); (T.H.W.); (N.G.); (D.K.); (H.E.W.); (P.S.); (C.T.)
| | - Elisa F. Brandt
- Department of Internal Medicine III, RWTH Aachen University, 52074 Aachen, Germany; (D.H.); (E.F.B.); (P.F.); (J.K.); (T.H.W.); (N.G.); (D.K.); (H.E.W.); (P.S.); (C.T.)
| | - Petra Fischer
- Department of Internal Medicine III, RWTH Aachen University, 52074 Aachen, Germany; (D.H.); (E.F.B.); (P.F.); (J.K.); (T.H.W.); (N.G.); (D.K.); (H.E.W.); (P.S.); (C.T.)
| | - Janine Köhncke
- Department of Internal Medicine III, RWTH Aachen University, 52074 Aachen, Germany; (D.H.); (E.F.B.); (P.F.); (J.K.); (T.H.W.); (N.G.); (D.K.); (H.E.W.); (P.S.); (C.T.)
| | - Theresa H. Wirtz
- Department of Internal Medicine III, RWTH Aachen University, 52074 Aachen, Germany; (D.H.); (E.F.B.); (P.F.); (J.K.); (T.H.W.); (N.G.); (D.K.); (H.E.W.); (P.S.); (C.T.)
| | - Nurdan Guldiken
- Department of Internal Medicine III, RWTH Aachen University, 52074 Aachen, Germany; (D.H.); (E.F.B.); (P.F.); (J.K.); (T.H.W.); (N.G.); (D.K.); (H.E.W.); (P.S.); (C.T.)
| | - Sonja Djudjaj
- Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany; (S.D.); (P.B.)
| | - Peter Boor
- Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany; (S.D.); (P.B.)
| | - Daniela Kroy
- Department of Internal Medicine III, RWTH Aachen University, 52074 Aachen, Germany; (D.H.); (E.F.B.); (P.F.); (J.K.); (T.H.W.); (N.G.); (D.K.); (H.E.W.); (P.S.); (C.T.)
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, 52074 Aachen, Germany;
| | - Richard Bucala
- Rheumatology Section of the Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8031, USA;
| | - Hermann E. Wasmuth
- Department of Internal Medicine III, RWTH Aachen University, 52074 Aachen, Germany; (D.H.); (E.F.B.); (P.F.); (J.K.); (T.H.W.); (N.G.); (D.K.); (H.E.W.); (P.S.); (C.T.)
| | - Pavel Strnad
- Department of Internal Medicine III, RWTH Aachen University, 52074 Aachen, Germany; (D.H.); (E.F.B.); (P.F.); (J.K.); (T.H.W.); (N.G.); (D.K.); (H.E.W.); (P.S.); (C.T.)
| | - Christian Trautwein
- Department of Internal Medicine III, RWTH Aachen University, 52074 Aachen, Germany; (D.H.); (E.F.B.); (P.F.); (J.K.); (T.H.W.); (N.G.); (D.K.); (H.E.W.); (P.S.); (C.T.)
| | - Jürgen Bernhagen
- Chair of Vascular Biology, Institute of Stroke and Dementia Research, LMU Klinikum, Lud-wig-Maximilian-University (LMU), 81377 Munich, Germany;
- Munich Cluster for Systems Neurology, 81377 Munich, Germany
| | - Marie-Luise Berres
- Department of Internal Medicine III, RWTH Aachen University, 52074 Aachen, Germany; (D.H.); (E.F.B.); (P.F.); (J.K.); (T.H.W.); (N.G.); (D.K.); (H.E.W.); (P.S.); (C.T.)
| |
Collapse
|
|
12
|
Enhanced oxidative phosphorylation in NKT cells is essential for their survival and function. Proc Natl Acad Sci U S A 2019; 116:7439-7448. [PMID: 30910955 DOI: 10.1073/pnas.1901376116] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Cellular metabolism and signaling pathways are key regulators to determine conventional T cell fate and function, but little is understood about the role of cell metabolism for natural killer T (NKT) cell survival, proliferation, and function. We found that NKT cells operate distinct metabolic programming from CD4 T cells. NKT cells are less efficient in glucose uptake than CD4 T cells with or without activation. Gene-expression data revealed that, in NKT cells, glucose is preferentially metabolized by the pentose phosphate pathway and mitochondria, as opposed to being converted into lactate. In fact, glucose is essential for the effector functions of NKT cells and a high lactate environment is detrimental for NKT cell survival and proliferation. Increased glucose uptake and IFN-γ expression in NKT cells is inversely correlated with bacterial loads in response to bacterial infection, further supporting the significance of glucose metabolism for NKT cell function. We also found that promyelocytic leukemia zinc finger seemed to play a role in regulating NKT cells' glucose metabolism. Overall, our study reveals that NKT cells use distinct arms of glucose metabolism for their survival and function.
Collapse
|
|
13
|
Berntsen NL, Fosby B, Tan C, Reims HM, Ogaard J, Jiang X, Schrumpf E, Valestrand L, Karlsen TH, Line PD, Blumberg RS, Melum E. Natural killer T cells mediate inflammation in the bile ducts. Mucosal Immunol 2018; 11:1582-1590. [PMID: 30115993 PMCID: PMC6402771 DOI: 10.1038/s41385-018-0066-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 06/29/2018] [Accepted: 07/09/2018] [Indexed: 02/04/2023]
Abstract
Cholangiocytes function as antigen-presenting cells with CD1d-dependent activation of natural killer T (NKT) cells in vitro. NKT cells may act both pro- and anti-inflammatory in liver immunopathology. We explored this immune pathway and the antigen-presenting potential of NKT cells in the bile ducts by challenging wild-type and Cd1d-/- mice with intrabiliary injection of the NKT cell activating agent oxazolone. Pharmacological blocking of CD1d-mediated activation was performed with a monoclonal antibody. Intrabiliary oxazolone injection in wild-type mice caused acute cholangitis with significant weight loss, elevated serum levels of alanine transaminase, aspartate transaminase, alkaline phosphatase and bilirubin, increased histologic grade of cholangitis and number of T cells, macrophages, neutrophils and myofibroblasts per portal tract after 7 days. NKT cells were activated after intrabiliary injection of oxazolone with upregulation of activation markers. Cd1d-/- and wild-type mice pretreated with antibody blocking of CD1d were protected from disease. These findings implicate that cells in the bile ducts function as antigen-presenting cells in vivo and activate NKT cells in a CD1d-restricted manner. The elucidation of this biliary immune pathway opens up for potentially new therapeutic approaches for cholangiopathies.
Collapse
Affiliation(s)
- N L Berntsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
| | - B Fosby
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - C Tan
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - H M Reims
- Department of Pathology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - J Ogaard
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
| | - X Jiang
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
| | - E Schrumpf
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
| | - L Valestrand
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
| | - T H Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
- Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - P-D Line
- Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - R S Blumberg
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - E Melum
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.
- Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| |
Collapse
|
|
14
|
The Role of Invariant NKT in Autoimmune Liver Disease: Can Vitamin D Act as an Immunomodulator? Can J Gastroenterol Hepatol 2018; 2018:8197937. [PMID: 30046564 PMCID: PMC6038587 DOI: 10.1155/2018/8197937] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 05/16/2018] [Indexed: 12/18/2022] Open
Abstract
Natural killer T (NKT) cells are a distinct lineage of T cells which express both the T cell receptor (TCR) and natural killer (NK) cell markers. Invariant NKT (iNKT) cells bear an invariant TCR and recognize a small variety of glycolipid antigens presented by CD1d (nonclassical MHC-I). CD1d-restricted iNKT cells are regulators of immune responses and produce cytokines that may be proinflammatory (such as interferon-gamma (IFN-γ)) or anti-inflammatory (such as IL-4). iNKT cells also appear to play a role in B cell regulation and antibody production. Alpha-galactosylceramide (α-GalCer), a derivative of the marine sponge, is a potent stimulator of iNKT cells and has been proposed as a therapeutic iNKT cell activator. Invariant NKT cells have been implicated in the development and perpetuation of several autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus (SLE). Animal models of SLE have shown abnormalities in iNKT cells numbers and function, and an inverse correlation between the frequency of NKT cells and IgG levels has also been observed. The role of iNKT cells in autoimmune liver disease (AiLD) has not been extensively studied. This review discusses the current data with regard to iNKT cells function in AiLD, in addition to providing an overview of iNKT cells function in other autoimmune conditions and animal models. We also discuss data regarding the immunomodulatory effects of vitamin D on iNKT cells, which may serve as a potential therapeutic target, given that deficiencies in vitamin D have been reported in various autoimmune disorders.
Collapse
|
|
15
|
|
|
16
|
Schönrich G, Raftery MJ. CD1-Restricted T Cells During Persistent Virus Infections: "Sympathy for the Devil". Front Immunol 2018; 9:545. [PMID: 29616036 PMCID: PMC5868415 DOI: 10.3389/fimmu.2018.00545] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 03/02/2018] [Indexed: 12/12/2022] Open
Abstract
Some of the clinically most important viruses persist in the human host after acute infection. In this situation, the host immune system and the viral pathogen attempt to establish an equilibrium. At best, overt disease is avoided. This attempt may fail, however, resulting in eventual loss of viral control or inadequate immune regulation. Consequently, direct virus-induced tissue damage or immunopathology may occur. The cluster of differentiation 1 (CD1) family of non-classical major histocompatibility complex class I molecules are known to present hydrophobic, primarily lipid antigens. There is ample evidence that both CD1-dependent and CD1-independent mechanisms activate CD1-restricted T cells during persistent virus infections. Sophisticated viral mechanisms subvert these immune responses and help the pathogens to avoid clearance from the host organism. CD1-restricted T cells are not only crucial for the antiviral host defense but may also contribute to tissue damage. This review highlights the two edged role of CD1-restricted T cells in persistent virus infections and summarizes the viral immune evasion mechanisms that target these fascinating immune cells.
Collapse
Affiliation(s)
- Günther Schönrich
- Berlin Institute of Health, Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Martin J Raftery
- Berlin Institute of Health, Institute of Virology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| |
Collapse
|
|
17
|
Exley MA, Wilson SB, Balk SP. Isolation and Functional Use of Human NKT Cells. ACTA ACUST UNITED AC 2017; 119:14.11.1-14.11.20. [PMID: 29091262 DOI: 10.1002/cpim.33] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This unit details methods for the isolation, in vitro expansion, and functional characterization of human iNKT cells. The term 'iNKT' derives from the fact that a large fraction of murine and some human NK marker+ T cells ('NKT') recognize the MHC class I-like CD1d protein and use an identical 'invariant' TCRα chain, which is generated in humans by precise Vα24 and Jα18 rearrangements with either no N-region diversity or subsequent trimming to identical or nearly identical amino acid sequence (hence, 'iNKT' cells). iNKT are mostly CD4+ or CD4-CD8- ('double negative'), although a few CD8+ iNKT can be found in some humans. Basic Protocol 1 and Alternate Protocol 1 use multi-color FACS analysis to identify and quantitate rare iNKT cells from human samples. Basic Protocol 2 describes iNKT cell purification. Alternate Protocol 2 describes a method for high-speed FACS sorting of iNKT cells. Basic Protocol 3 explains functional analysis of iNKT. Alternate Protocol 3 employs a cell sorting approach to isolate iNKT cell clones. A support protocol for secondary stimulation and rapid expansion of iNKT cells is also included. © 2017 by John Wiley & Sons, Inc.
Collapse
Affiliation(s)
- Mark A Exley
- Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.,Manchester Collaborative Centre for Inflammation Research, Manchester, United Kingdom
| | - S Brian Wilson
- Diabetes Center of Excellence, University of Florida, Gainesville, Florida
| | - Steven P Balk
- Cancer Biology Program, Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| |
Collapse
|
|
18
|
Weng X, He Y, Visvabharathy L, Liao CM, Tan X, Balakumar A, Wang CR. Crosstalk between type II NKT cells and T cells leads to spontaneous chronic inflammatory liver disease. J Hepatol 2017; 67:791-800. [PMID: 28596110 PMCID: PMC5605413 DOI: 10.1016/j.jhep.2017.05.024] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Revised: 04/28/2017] [Accepted: 05/23/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIM Natural killer T (NKT) cells are CD1d-restricted innate-like T cells that modulate innate and adaptive immune responses. Unlike the well-characterized invariant/type I NKT cells, type II NKT cells with a diverse T cell receptor repertoire are poorly understood. This study defines the pathogenic role of type II NKT cells in the etiology of chronic liver inflammation. METHODS Transgenic mice with the Lck promoter directing CD1d overexpression on T cells in Jα18 wild-type (Lck-CD1dTgJα18+; type I NKT cell sufficient) and Jα18-deficient (Lck-CD1dTgJα18o, type I NKT cell deficient) mice were analyzed for liver pathology and crosstalk between type II NKT cells and conventional T cells. CD1d expression on T cells in peripheral blood samples and liver sections from autoimmune hepatitis patients and healthy individuals were also examined. RESULTS Lck-CD1dTgJα18o and Lck-CD1dTgJα18+ mice developed similar degrees of liver pathology resembling chronic autoimmune hepatitis in humans. Increased CD1d expression on T cells promoted the activation of type II NKT cells and other T cells. This resulted in Th1-skewing and impaired Th2 cytokine production in type II NKT cells. Dysfunction of type II NKT cells was accompanied by conventional T cell activation and pro-inflammatory cytokine production, leading to a hepatic T/B lymphocyte infiltration, elevated autoantibodies and hepatic injury in Lck-CD1dTg mice. A similar mechanism could be extended to humans as CD1d expression is upregulated on activated human T cells and increased presence of CD1d-expressing T cells was observed in autoimmune hepatitis patients. CONCLUSIONS Our data reveals enhanced crosstalk between type II NKT cells and conventional T cells, leading to a Th1-skewed inflammatory milieu, and consequently, to the development of chronic autoimmune liver disease. Lay summary: CD1d overexpression on T cells enhances crosstalk between type II NKT cells and T cells, resulting in their aberrant activation and leading to the development of chronic autoimmune liver disease.
Collapse
Affiliation(s)
- Xiufang Weng
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States; Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Ying He
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Lavanya Visvabharathy
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Chia-Min Liao
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Xiaosheng Tan
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Arjun Balakumar
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Chyung-Ru Wang
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States.
| |
Collapse
|
|
19
|
Dasgupta S, Kumar V. Type II NKT cells: a distinct CD1d-restricted immune regulatory NKT cell subset. Immunogenetics 2016; 68:665-76. [PMID: 27405300 PMCID: PMC6334657 DOI: 10.1007/s00251-016-0930-1] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 06/22/2016] [Indexed: 12/16/2022]
Abstract
Type II natural killer T cells (NKT) are a subset of the innate-like CD1d-restricted lymphocytes that are reactive to lipid antigens. Unlike the type I NKT cells, which express a semi-invariant TCR, type II NKT cells express a broader TCR repertoire. Additionally, other features, such as their predominance over type I cells in humans versus mice, the nature of their ligands, CD1d/lipid/TCR binding, and modulation of immune responses, distinguish type II NKT cells from type I NKT cells. Interestingly, it is the self-lipid-reactivity of type II NKT cells that has helped define their physiological role in health and in disease. The discovery of sulfatide as one of the major antigens for CD1d-restricted type II NKT cells in mice has been instrumental in the characterization of these cells, including the TCR repertoire, the crystal structure of the CD1d/lipid/TCR complex, and their function. Subsequently, several other glycolipids and phospholipids from both endogenous and microbial sources have been shown to activate type II NKT cells. The activation of a specific subset of type II NKT cells following administration with sulfatide or lysophosphatidylcholine (LPC) leads to engagement of a dominant immunoregulatory pathway associated with the inactivation of type I NKT cells, conventional dendritic cells, and inhibition of the proinflammatory Th1/Th17 cells. Thus, type II NKT cells have been shown to be immunosuppressive in autoimmune diseases, inflammatory liver diseases, and in cancer. Knowing their relatively higher prevalence in human than type I NKT cells, understanding their biology is imperative for health and disease.
Collapse
Affiliation(s)
- Suryasarathi Dasgupta
- Division of Gastroenterology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92037, USA
| | - Vipin Kumar
- Division of Gastroenterology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92037, USA.
| |
Collapse
|
|
20
|
Diagnostic performance of T lymphocyte subpopulations in assessment of liver fibrosis stages in hepatitis C virus patients: simple noninvasive score. Eur J Gastroenterol Hepatol 2016; 28:931-9. [PMID: 27159125 DOI: 10.1097/meg.0000000000000656] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
BACKGROUND/AIMS Evaluation of liver fibrosis in patients infected with hepatitis C virus is highly useful for the diagnosis of the disease as well as therapeutic decision. Our aim was to develop and validate a simple noninvasive score for liver fibrosis staging in chronic hepatitis C (CHC) patients and compare its performance against three published simple noninvasive indexes. MATERIALS AND METHODS CHC patients were divided into two groups: an estimated group (n=70) and a validated group (n=52). Liver fibrosis was tested in biopsies using the Metavair score system. CD4 and CD8 count/percentage were assayed by fluorescence-activated cell sorting analysis. RESULTS The multivariate discriminant analysis selects a function on the basis of absolute values of five biochemical markers: immune fibrosis index (IFI); score=3.07+3.06×CD4/CD8+0.02×α-fetoprotein (U/l)-0.07×alanine aminotransferase ratio-0.005×platelet count (10/l)-1.4×albumin (g/dl). The IFI score produced areas under curve of 0.949, 0.947, and 0.806 for differentiation of all patient categories [significant fibrosis (F2-F4), advanced fibrosis (F3-F4), and cirrhosis (F4)]. CONCLUSION The IFI score, a novel noninvasive test, can be used easily for the prediction of liver fibrosis stage in CHC patients. Our score was more efficient than aspartate aminotransferase to platelet ratio index, fibrosis index, and fibroQ and more suitable for use in Egyptian hepatitis C virus patients.
Collapse
|
|
21
|
Sebode M, Schramm C. Natural killer T cells: novel players in biliary disease? Hepatology 2015; 62:999-1000. [PMID: 25914184 DOI: 10.1002/hep.27862] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Accepted: 04/19/2015] [Indexed: 12/16/2022]
Affiliation(s)
- Marcial Sebode
- 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| |
Collapse
|
|
22
|
Schrumpf E, Tan C, Karlsen TH, Sponheim J, Björkström NK, Sundnes O, Alfsnes K, Kaser A, Jefferson DM, Ueno Y, Eide TJ, Haraldsen G, Zeissig S, Exley MA, Blumberg RS, Melum E. The biliary epithelium presents antigens to and activates natural killer T cells. Hepatology 2015; 62:1249-59. [PMID: 25855031 PMCID: PMC4589438 DOI: 10.1002/hep.27840] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Accepted: 04/07/2015] [Indexed: 02/02/2023]
Abstract
UNLABELLED Cholangiocytes express antigen-presenting molecules, but it has been unclear whether they can present antigens. Natural killer T (NKT) cells respond to lipid antigens presented by the major histocompatibility complex class I-like molecule CD1d and are abundant in the liver. We investigated whether cholangiocytes express CD1d and present lipid antigens to NKT cells and how CD1d expression varies in healthy and diseased bile ducts. Murine and human cholangiocyte cell lines as well as human primary cholangiocytes expressed CD1d as determined by flow cytometry and western blotting. Murine cholangiocyte cell lines were able to present both exogenous and endogenous lipid antigens to invariant and noninvariant NKT cell hybridomas and primary NKT cells in a CD1d-dependent manner. A human cholangiocyte cell line, cholangiocarcinoma cell lines, and human primary cholangiocytes also presented exogenous CD1d-restricted antigens to invariant NKT cell clones. CD1d expression was down-regulated in the biliary epithelium of patients with late primary sclerosing cholangitis, primary biliary cirrhosis, and alcoholic cirrhosis compared to healthy controls. CONCLUSIONS Cholangiocytes express CD1d and present antigens to NKT cells and CD1d expression is down-regulated in diseased biliary epithelium, findings which show that the biliary epithelium can activate an important lymphocyte subset of the liver. This is a potentially important immune pathway in the biliary system, which may be capable of regulating inflammation in the context of biliary disease.
Collapse
Affiliation(s)
- Elisabeth Schrumpf
- Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Corey Tan
- Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Tom H. Karlsen
- Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Jon Sponheim
- K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Laboratory of Immunohistochemistry and Immunopathology, Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Niklas K. Björkström
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- Liver Immunology Laboratory, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Olav Sundnes
- Laboratory of Immunohistochemistry and Immunopathology, Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- K.G. Jebsen Inflammation Research Centre, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Kristian Alfsnes
- Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Arthur Kaser
- Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Douglas M. Jefferson
- Department of Integrative Physiology and Pathobiology, Sackler School, Tufts University School of Medicine, Boston, MA, USA
| | - Yoshiyuki Ueno
- Division of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Tor J. Eide
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Guttorm Haraldsen
- Laboratory of Immunohistochemistry and Immunopathology, Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- K.G. Jebsen Inflammation Research Centre, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Sebastian Zeissig
- Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Mark A. Exley
- Manchester Collaborative Centre for Inflammation Research (MCCIR), Faculty of Medical & Human Sciences, University of Manchester, Manchester, UK
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Richard S. Blumberg
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Espen Melum
- Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| |
Collapse
|
|
23
|
Macho-Fernandez E, Brigl M. The Extended Family of CD1d-Restricted NKT Cells: Sifting through a Mixed Bag of TCRs, Antigens, and Functions. Front Immunol 2015; 6:362. [PMID: 26284062 PMCID: PMC4517383 DOI: 10.3389/fimmu.2015.00362] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 07/04/2015] [Indexed: 01/21/2023] Open
Abstract
Natural killer T (NKT) cells comprise a family of specialized T cells that recognize lipid antigens presented by CD1d. Based on their T cell receptor (TCR) usage and antigen specificities, CD1d-restricted NKT cells have been divided into two main subsets: type I NKT cells that use a canonical invariant TCR α-chain and recognize α-galactosylceramide (α-GalCer), and type II NKT cells that use a more diverse αβ TCR repertoire and do not recognize α-GalCer. In addition, α-GalCer-reactive NKT cells that use non-canonical αβ TCRs and CD1d-restricted T cells that use γδ or δ/αβ TCRs have recently been identified, revealing further diversity among CD1d-restricted T cells. Importantly, in addition to their distinct antigen specificities, functional differences are beginning to emerge between the different members of the CD1d-restricted T cell family. In this review, while using type I NKT cells as comparison, we will focus on type II NKT cells and the other non-invariant CD1d-restricted T cell subsets, and discuss our current understanding of the antigens they recognize, the formation of stimulatory CD1d/antigen complexes, the modes of TCR-mediated antigen recognition, and the mechanisms and consequences of their activation that underlie their function in antimicrobial responses, anti-tumor immunity, and autoimmunity.
Collapse
Affiliation(s)
- Elodie Macho-Fernandez
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Manfred Brigl
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
24
|
Opasawatchai A, Matangkasombut P. iNKT Cells and Their Potential Lipid Ligands during Viral Infection. Front Immunol 2015; 6:378. [PMID: 26257744 PMCID: PMC4513233 DOI: 10.3389/fimmu.2015.00378] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2015] [Accepted: 07/11/2015] [Indexed: 01/12/2023] Open
Abstract
Invariant natural killer T (iNKT) cells are a unique population of lipid-reactive CD1d-restricted innate-like T lymphocytes. Despite being a minor population, they serve as an early source of cytokines and promote immunological crosstalk thus bridging innate and adaptive immunity. Diseases ranging from allergy, autoimmunity, and cancer, as well as infectious diseases, including viral infection, have been reported to be influenced by iNKT cells. However, it remains unclear how iNKT cells are activated during viral infection, as virus-derived lipid antigens have not been reported. Cytokines may activate iNKT cells during infections from influenza and murine cytomegalovirus, although CD1d-dependent activation is evident in other viral infections. Several viruses, such as dengue virus, induce CD1d upregulation, which correlates with iNKT cell activation. In contrast, herpes simplex virus type 1 (HSV-1), human immunodeficiency virus (HIV), Epstein–Barr virus, and human papilloma virus promote CD1d downregulation as a strategy to evade iNKT cell recognition. These observations suggest the participation of a CD1d-dependent process in the activation of iNKT cells in response to viral infection. Endogenous lipid ligands, including phospholipids as well as glycosphingolipids, such as glucosylceramide, have been proposed to mediate iNKT cell activation. Pro-inflammatory signals produced during viral infection may stimulate iNKT cells through enhanced CD1d-dependent endogenous lipid presentation. Furthermore, viral infection may alter lipid composition and inhibit endogenous lipid degradation. Recent advances in this field are reviewed.
Collapse
Affiliation(s)
- Anunya Opasawatchai
- Department of Microbiology, Faculty of Science, Mahidol University , Bangkok , Thailand ; Faculty of Dentistry, Mahidol University , Bangkok , Thailand
| | - Ponpan Matangkasombut
- Department of Microbiology, Faculty of Science, Mahidol University , Bangkok , Thailand ; Systems Biology of Diseases Research Unit, Faculty of Science, Mahidol University , Bangkok , Thailand
| |
Collapse
|
|
25
|
Pathogen-expanded CD11b+ invariant NKT cells feedback inhibit T cell proliferation via membrane-bound TGF-β1. J Autoimmun 2015; 58:21-35. [DOI: 10.1016/j.jaut.2014.12.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Revised: 12/13/2014] [Accepted: 12/21/2014] [Indexed: 12/23/2022]
|
|
26
|
Invariant Natural Killer T Cells are Reduced in Hereditary Hemochromatosis Patients. J Clin Immunol 2014; 35:68-74. [DOI: 10.1007/s10875-014-0118-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Accepted: 11/27/2014] [Indexed: 01/25/2023]
|
|
27
|
Matangkasombut P, Chan-in W, Opasawaschai A, Pongchaikul P, Tangthawornchaikul N, Vasanawathana S, Limpitikul W, Malasit P, Duangchinda T, Screaton G, Mongkolsapaya J. Invariant NKT cell response to dengue virus infection in human. PLoS Negl Trop Dis 2014; 8:e2955. [PMID: 24945350 PMCID: PMC4063705 DOI: 10.1371/journal.pntd.0002955] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Accepted: 05/07/2014] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Dengue viral infection is a global health threat without vaccine or specific treatment. The clinical outcome varies from asymptomatic, mild dengue fever (DF) to severe dengue hemorrhagic fever (DHF). While adaptive immune responses were found to be detrimental in the dengue pathogenesis, the roles of earlier innate events remain largely uninvestigated. Invariant natural killer T (iNKT) cells represent innate-like T cells that could dictate subsequent adaptive response but their role in human dengue virus infection is not known. We hypothesized that iNKT cells play a role in human dengue infection. METHODS Blood samples from a well-characterized cohort of children with DF, DHF, in comparison to non-dengue febrile illness (OFI) and healthy controls at various time points were studied. iNKT cells activation were analyzed by the expression of CD69 by flow cytometry. Their cytokine production was then analyzed after α-GalCer stimulation. Further, the CD1d expression on monocytes, and CD69 expression on conventional T cells were measured. RESULTS iNKT cells were activated during acute dengue infection. The level of iNKT cell activation associates with the disease severity. Furthermore, these iNKT cells had altered functional response to subsequent ex vivo stimulation with α-GalCer. Moreover, during acute dengue infection, monocytic CD1d expression was also upregulated and conventional T cells also became activated. CONCLUSION iNKT cells might play an early and critical role in the pathogenesis of severe dengue viral infection in human. Targeting iNKT cells and CD1d serve as a potential therapeutic strategy for severe dengue infection in the future.
Collapse
Affiliation(s)
- Ponpan Matangkasombut
- Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand
- Systems Biology of Diseases Research Unit, Faculty of Science, Mahidol University, Bangkok, Thailand
- Center of Emerging and Neglected Infectious Diseases, Mahidol University, Bangkok, Thailand
| | - Wilawan Chan-in
- Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Anunya Opasawaschai
- Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Pisut Pongchaikul
- Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Nattaya Tangthawornchaikul
- Medical Biotechnology Unit, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathumthani, Thailand
| | | | | | - Prida Malasit
- Center of Emerging and Neglected Infectious Diseases, Mahidol University, Bangkok, Thailand
- Medical Biotechnology Unit, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathumthani, Thailand
- Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Thaneeya Duangchinda
- Center of Emerging and Neglected Infectious Diseases, Mahidol University, Bangkok, Thailand
- Medical Biotechnology Unit, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathumthani, Thailand
| | - Gavin Screaton
- Division of Immunology and Inflammation, Department of Medicine, Hammersmith campus, Imperial College London, London, United Kingdom
| | - Juthathip Mongkolsapaya
- Center of Emerging and Neglected Infectious Diseases, Mahidol University, Bangkok, Thailand
- Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Division of Immunology and Inflammation, Department of Medicine, Hammersmith campus, Imperial College London, London, United Kingdom
| |
Collapse
|
|
28
|
Mastroianni CM, Lichtner M, Mascia C, Zuccalà P, Vullo V. Molecular mechanisms of liver fibrosis in HIV/HCV coinfection. Int J Mol Sci 2014; 15:9184-208. [PMID: 24865485 PMCID: PMC4100089 DOI: 10.3390/ijms15069184] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Revised: 05/15/2014] [Accepted: 05/15/2014] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is an important cause of morbidity and mortality in people coinfected with human immunodeficiency virus (HIV). Several studies have shown that HIV infection promotes accelerated HCV hepatic fibrosis progression, even with HIV replication under full antiretroviral control. The pathogenesis of accelerated hepatic fibrosis among HIV/HCV coinfected individuals is complex and multifactorial. The most relevant mechanisms involved include direct viral effects, immune/cytokine dysregulation, altered levels of matrix metalloproteinases and fibrosis biomarkers, increased oxidative stress and hepatocyte apoptosis, HIV-associated gut depletion of CD4 cells, and microbial translocation. In addition, metabolic alterations, heavy alcohol use, as well drug use, may have a potential role in liver disease progression. Understanding the pathophysiology and regulation of liver fibrosis in HIV/HCV co-infection may lead to the development of therapeutic strategies for the management of all patients with ongoing liver disease. In this review, we therefore discuss the evidence and potential molecular mechanisms involved in the accelerated liver fibrosis seen in patients coinfected with HIV and HCV.
Collapse
Affiliation(s)
- Claudio M Mastroianni
- Department of Public Health and Infectious Diseases, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Miriam Lichtner
- Department of Public Health and Infectious Diseases, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Claudia Mascia
- Department of Public Health and Infectious Diseases, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Paola Zuccalà
- Department of Public Health and Infectious Diseases, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Vincenzo Vullo
- Department of Public Health and Infectious Diseases, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| |
Collapse
|
|
29
|
Diao H, He J, Zheng Q, Chen J, Cui G, Wei Y, Ye P, Kohanawa M, Li L. A possible role for NKT-like cells in patients with chronic hepatitis B during telbivudine treatment. Immunol Lett 2014; 160:65-71. [PMID: 24718278 DOI: 10.1016/j.imlet.2014.03.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 03/21/2014] [Accepted: 03/28/2014] [Indexed: 12/23/2022]
Abstract
Natural killer T-like (NKT-like) cells are a source of different pro-inflammatory cytokines and therefore may be involved in inflammatory processes. However, little is known about NKT-like cells during antiviral therapy. In this study, we observed significantly higher numbers of CD3(+)CD56(+) cells in patients with chronic hepatitis B (CHB) than healthy controls. Importantly, CD3(+)CD56(+) NKT-like cells markedly decreased during telbivudine treatment in patients with CHB, and a positive correlation between NKT-like cell frequency and the serum HBV DNA level was observed during early antiviral therapy. Interestingly, NKT-like cell frequency significantly reduced in well-responders at week 12 of telbivudine therapy compared to baseline, but did not significantly change in non-responders after treatment. Previous studies have shown that interleukin (IL)-17 plays a role in the pathogenesis of CHB. Serum IL-17 levels reduced significantly during early antiviral therapy, however, interferon (IFN)-γ, IL-6 and tumor necrosis factor (TNF)-α levels did not change significantly. A positive correlation was observed between the NKT-like cell frequency and serum IL-17 level in CHB patients, and NKT-like cells isolated from patients with CHB secreted substantial amounts of IL-17 in vitro. These results suggest that the NKT-like cell frequency may be one of useful immunologic marker for evaluating the efficacy of anti-HBV therapy, and that NKT-like cells are also an important source of IL-17 (in addition to conventional T cells) in patients with CHB.
Collapse
Affiliation(s)
- Hongyan Diao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
| | - Jianqin He
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Qishi Zheng
- The College of Education, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Jianing Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Guangying Cui
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Yingfeng Wei
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Ping Ye
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Masashi Kohanawa
- Department of Microbiology, School of Medicine, Hokkaido University, Sapporo 0600815, Japan
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
| |
Collapse
|
|
30
|
Polyclonal type II natural killer T cells require PLZF and SAP for their development and contribute to CpG-mediated antitumor response. Proc Natl Acad Sci U S A 2014; 111:2674-9. [PMID: 24550295 DOI: 10.1073/pnas.1323845111] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
CD1d-restricted natural killer T (NKT) cells are innate-like T cells with potent immunomodulatory function via rapid production of both Th1 and Th2 cytokines. NKT cells comprise well-characterized type I NKT cells, which can be detected by α-galactosylceramide-loaded CD1d tetramers, and less-studied type II NKT cells, which do not recognize α-galactosylceramide. Here we characterized type II NKT cells on a polyclonal level by using a Jα18-deficient IL-4 reporter mouse model. This model allows us to track type II NTK cells by the GFP(+)TCRβ(+) phenotype in the thymus and liver. We found type II NKT cells, like type I NKT cells, exhibit an activated phenotype and are dependent on the transcriptional regulator promyelocytic leukemia zinc finger (PLZF) and the adaptor molecule signaling lymphocyte activation molecule-associated protein (SAP) for their development. Type II NKT cells are potently activated by β-D-glucopyranosylceramide (β-GlcCer) but not sulfatide or phospholipids in a CD1d-dependent manner, with the stimulatory capacity of β-GlcCer influenced by acyl chain length. Compared with type I NKT cells, type II NKT cells produce lower levels of IFN-γ but comparable amounts of IL-13 in response to polyclonal T-cell receptor stimulation, suggesting they may play different roles in regulating immune responses. Furthermore, type II NKT cells can be activated by CpG oligodeoxynucletides to produce IFN-γ, but not IL-4 or IL-13. Importantly, CpG-activated type II NKT cells contribute to the antitumor effect of CpG in the B16 melanoma model. Taken together, our data reveal the characteristics of polyclonal type II NKT cells and their potential role in antitumor immunotherapy.
Collapse
|
|
31
|
Guabiraba R, Ryffel B. Dengue virus infection: current concepts in immune mechanisms and lessons from murine models. Immunology 2014; 141:143-56. [PMID: 24182427 PMCID: PMC3904235 DOI: 10.1111/imm.12188] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Revised: 10/07/2013] [Accepted: 10/08/2013] [Indexed: 12/21/2022] Open
Abstract
Dengue viruses (DENV), a group of four serologically distinct but related flaviviruses, are responsible for one of the most important emerging viral diseases. This mosquito-borne disease has a great impact in tropical and subtropical areas of the world in terms of illness, mortality and economic costs, mainly due to the lack of approved vaccine or antiviral drugs. Infections with one of the four serotypes of DENV (DENV-1-4) result in symptoms ranging from an acute, self-limiting febrile illness, dengue fever, to severe dengue haemorrhagic fever or dengue shock syndrome. We reviewed the existing mouse models of infection, including the DENV-2-adapted strain P23085. The role of CC chemokines, interleukin-17 (IL-17), IL-22 and invariant natural killer T cells in mediating the exacerbation of disease in immune-competent mice is highlighted. Investigations in both immune-deficient and immune-competent mouse models of DENV infection may help to identify key host–pathogen factors and devise novel therapies to restrain the systemic and local inflammatory responses associated with severe DENV infection.
Collapse
Affiliation(s)
- Rodrigo Guabiraba
- Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, College of Medical, Veterinary and Life Sciences, University of GlasgowGlasgow, UK
- Université d’Orléans and CNRS, UMR 7355 Molecular and Experimental Immunology and NeurogeneticsOrléans, France
| | - Bernhard Ryffel
- Université d’Orléans and CNRS, UMR 7355 Molecular and Experimental Immunology and NeurogeneticsOrléans, France
- IIDMM, UCTCape Town, South Africa
- Artimmune SASOrléans, France
| |
Collapse
|
|
32
|
Martin-Murphy BV, You Q, Wang H, De La Houssaye BA, Reilly TP, Friedman JE, Ju C. Mice lacking natural killer T cells are more susceptible to metabolic alterations following high fat diet feeding. PLoS One 2014; 9:e80949. [PMID: 24465369 PMCID: PMC3896335 DOI: 10.1371/journal.pone.0080949] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2013] [Accepted: 10/14/2013] [Indexed: 12/12/2022] Open
Abstract
Current estimates suggest that over one-third of the adult population has metabolic syndrome and three-fourths of the obese population has non-alcoholic fatty liver disease (NAFLD). Inflammation in metabolic tissues has emerged as a universal feature of obesity and its co-morbidities, including NAFLD. Natural Killer T (NKT) cells are a subset of innate immune cells that abundantly reside within the liver and are readily activated by lipid antigens. There is general consensus that NKT cells are pivotal regulators of inflammation; however, disagreement exists as to whether NKT cells exert pathogenic or suppressive functions in obesity. Here we demonstrate that CD1d−/− mice, which lack NKT cells, were more susceptible to weight gain and fatty liver following high fat diet (HFD) feeding. Compared with their WT counterparts, CD1d−/− mice displayed increased adiposity and greater induction of inflammatory genes in the liver suggestive of the precursors of NAFLD. Calorimetry studies revealed a significant increase in food intake and trends toward decreased metabolic rate and activity in CD1d−/− mice compared with WT mice. Based on these findings, our results suggest that NKT cells play a regulatory role that helps to prevent diet-induced obesity and metabolic dysfunction and may play an important role in mechanisms governing cross-talk between metabolism and the immune system to regulate energy balance and liver health.
Collapse
Affiliation(s)
- Brittany V. Martin-Murphy
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Qiang You
- Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Hong Wang
- Division of Endocrinology, Diabetes & Metabolism, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Becky A. De La Houssaye
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Timothy P. Reilly
- Drug Safety Evaluation, Research & Development, Bristol-Myers Squibb Company, Princeton, New Jersey, United States of America
| | - Jacob E. Friedman
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Cynthia Ju
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
- * E-mail:
| |
Collapse
|
|
33
|
Kadri N, Blomqvist M, Cardell SL. Type II natural killer T cells: a new target for immunomodulation? Expert Rev Clin Immunol 2014; 4:615-27. [DOI: 10.1586/1744666x.4.5.615] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
|
|
34
|
Werner JM, Heller T, Gordon AM, Sheets A, Sherker AH, Kessler E, Bean KS, Stevens M, Schmitt J, Rehermann B. Innate immune responses in hepatitis C virus-exposed healthcare workers who do not develop acute infection. Hepatology 2013; 58:1621-31. [PMID: 23463364 PMCID: PMC3688637 DOI: 10.1002/hep.26353] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2012] [Accepted: 02/16/2013] [Indexed: 12/11/2022]
Abstract
UNLABELLED Hepatitis C virus (HCV) infection typically results in chronic disease with HCV outpacing antiviral immune responses. Here we asked whether innate immune responses are induced in healthcare workers who are exposed to small amounts of HCV, but do not develop systemic infection and acute liver disease. Twelve healthcare workers with accidental percutaneous exposure to HCV-infected blood were prospectively studied for up to 6 months for phenotype and function of natural killer T (NKT) and NK cells, kinetics of serum chemokines, and vigor and specificity of HCV-specific T-cell responses. Eleven healthcare workers tested negative for HCV RNA and HCV antibodies. All but one of these aviremic cases displayed NKT cell activation, increased serum chemokines levels, and NK cell responses with increased CD122, NKp44, NKp46, and NKG2A expression, cytotoxicity (as determined by TRAIL and CD107a expression), and interferon-gamma (IFN-γ) production. This multifunctional NK cell response appeared a month earlier than in the one healthcare worker who developed high-level viremia, and it differed from the impaired IFN-γ production, which is typical for NK cells in chronic HCV infection. The magnitude of NKT cell activation and NK cell cytotoxicity correlated with the magnitude of the subsequent HCV-specific T-cell response. T-cell responses targeted nonstructural HCV sequences that require translation of viral RNA, which suggests that transient or locally contained HCV replication occurred without detectable systemic viremia. CONCLUSION Exposure to small amounts of HCV induces innate immune responses, which correlate with the subsequent HCV-specific T-cell response and may contribute to antiviral immunity.
Collapse
Affiliation(s)
- Jens Martin Werner
- Liver Diseases Branch, NIDDK, National Institutes of Health, DHHS, 10 Center Drive, Bethesda, MD 20892-1800, USA
| | - Theo Heller
- Liver Diseases Branch, NIDDK, National Institutes of Health, DHHS, 10 Center Drive, Bethesda, MD 20892-1800, USA
| | - Ann Marie Gordon
- Occupational Health, Medstar Washington Hospital Center, 110 Irving Street, NW, Washington, DC 20010, USA
| | - Arlene Sheets
- Occupational Health, Medstar Washington Hospital Center, 110 Irving Street, NW, Washington, DC 20010, USA
| | - Averell H. Sherker
- Center for Liver Diseases, Washington Hospital Center, 110 Irving Street, NW, Washington, DC 20010, USA
| | - Ellen Kessler
- Employee Occupational Health, Inova Fairfax Hospital, 3300 Gallows Road Falls Church, VA 22042, USA
| | - Kathleen S. Bean
- Employee Occupational Health, Inova Fairfax Hospital, 3300 Gallows Road Falls Church, VA 22042, USA
| | - M'Lou Stevens
- Occupational Medical Service, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1584, USA
| | - James Schmitt
- Occupational Medical Service, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1584, USA
| | - Barbara Rehermann
- Liver Diseases Branch, NIDDK, National Institutes of Health, DHHS, 10 Center Drive, Bethesda, MD 20892-1800, USA
| |
Collapse
|
|
35
|
Yanagisawa K, Yue S, van der Vliet HJ, Wang R, Alatrakchi N, Golden-Mason L, Schuppan D, Koziel MJ, Rosen HR, Exley MA. Ex vivo analysis of resident hepatic pro-inflammatory CD1d-reactive T cells and hepatocyte surface CD1d expression in hepatitis C. J Viral Hepat 2013; 20:556-65. [PMID: 23808994 PMCID: PMC4054599 DOI: 10.1111/jvh.12081] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Accepted: 12/12/2012] [Indexed: 12/20/2022]
Abstract
Hepatic CD1d-restricted and natural killer T-cell populations are heterogeneous. Classical 'type 1' α-galactosylceramide-reactive CD1d-restricted T cells express 'invariant' TCRα ('iNKT'). iNKT dominating rodent liver are implicated in inflammation, including in hepatitis models. Low levels of iNKT are detected in human liver, decreased in subjects with chronic hepatitis C (CHC). However, high levels of human hepatic CD161(±) CD56(±) noninvariant pro-inflammatory CD1d-restricted 'type 2' T cells have been identified in vitro. Unlike rodents, healthy human hepatocytes only express trace and intracellular CD1d. Total hepatic CD1d appears to be increased in CHC and primary biliary cirrhosis. Direct ex vivo analysis of human intrahepatic lymphocytes (IHL), including matched ex vivo versus in vitro expanded IHL, demonstrated detectable noninvariant CD1d reactivity in substantial proportions of HCV-positive livers and significant fractions of HCV-negative livers. However, α-galactosylceramide-reactive iNKT were detected only relatively rarely. Liver CD1d-restricted IHL produced IFNγ, variable levels of IL-10 and modest levels of Th2 cytokines IL-4 and IL-13 ex vivo. In a novel FACS assay, a major fraction (10-20%) of hepatic T cells rapidly produced IFNγ and up-regulated activation marker CD69 in response to CD1d. As previously only shown with murine iNKT, noninvariant human CD1d-specific responses were also augmented by IL-12. Interestingly, CD1d was found selectively expressed on the surface of hepatocytes in CHC, but not those CHC subjects with history of alcohol usage or resolved CHC. In contrast to hepatic iNKT, noninvariant IFNγ-producing type 2 CD1d-reactive NKT cells are commonly detected in CHC, together with cognate ligand CD1d, implicating them in CHC liver damage.
Collapse
Affiliation(s)
- Kazuhiko Yanagisawa
- Medicine; Beth Israel Deaconess Medical Ctr; Harvard Medical School, Boston, MA
| | - Simon Yue
- Medicine; Beth Israel Deaconess Medical Ctr; Harvard Medical School, Boston, MA
| | | | - RuoJie Wang
- Medicine; Beth Israel Deaconess Medical Ctr; Harvard Medical School, Boston, MA
| | - Nadia Alatrakchi
- Medicine; Beth Israel Deaconess Medical Ctr; Harvard Medical School, Boston, MA
| | - Lucy Golden-Mason
- Gastroenterology/Hepatology, University of Colorado Denver Health Sciences Center, Denver, CO
| | - Detlef Schuppan
- Medicine; Beth Israel Deaconess Medical Ctr; Harvard Medical School, Boston, MA
| | - Margaret J. Koziel
- Medicine; Beth Israel Deaconess Medical Ctr; Harvard Medical School, Boston, MA
| | - Hugo R. Rosen
- Gastroenterology/Hepatology, University of Colorado Denver Health Sciences Center, Denver, CO
| | - Mark A. Exley
- Medicine; Beth Israel Deaconess Medical Ctr; Harvard Medical School, Boston, MA
| |
Collapse
|
|
36
|
Cross-regulation of T regulatory-cell response after coxsackievirus B3 infection by NKT and γδ T cells in the mouse. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 183:441-9. [PMID: 23746656 DOI: 10.1016/j.ajpath.2013.04.015] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2012] [Revised: 03/21/2013] [Accepted: 04/12/2013] [Indexed: 01/04/2023]
Abstract
Coxsackievirus B3 (CVB3) variants H3 and H310A1 differ by a single nonconserved amino acid in the VP2 capsid region. C57Bl/6 mice infected with the H3 virus develop myocarditis correlating with activation of T cells expressing the Vγ4 T cell receptor chain. Infecting mice with H310A1 activates natural killer T (NKT; mCD1d-tetramer(+) TCRβ(+)) cells, but not Vγ4 T cells, and fails to induce myocarditis. H310A1 infection preferentially activates M2 alternatively activated macrophage and CD4(+)FoxP3 (T regulatory) cells, whereas CD4(+)Th1 (IFN-γ(+)) cells are suppressed. By contrast, H3 virus infection activates M1 proinflammatory and CD4(+)Th1 cells, but not T regulatory cells. The M1 macrophage show significantly increased CD1d expression compared to M2 macrophage. The ability of NKT cells to suppress myocarditis was shown by adoptive transfer of purified NKT cells into H3-infected NKT knockout (Jα18 knockout) mice, which inhibited cardiac inflammation and increased T regulatory cell response. Cardiac virus titers were equivalent in all mouse strains indicating that neither Vγ4 nor NKT cells participate in control of virus infection. These data show that NKT and Vγ4 cells cross-regulate T regulatory cell responses during CVB3 infections and are the primary factor determining viral pathogenesis in this mouse model.
Collapse
|
|
37
|
Lack of PD-L1 expression by iNKT cells improves the course of influenza A infection. PLoS One 2013; 8:e59599. [PMID: 23555047 PMCID: PMC3598698 DOI: 10.1371/journal.pone.0059599] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Accepted: 02/19/2013] [Indexed: 01/12/2023] Open
Abstract
There is evidence indicating that invariant Natural Killer T (iNKT) cells play an important role in defense against influenza A virus (IAV). However, the effect of inhibitory receptor, programmed death-1 (PD-1), and its ligands, programmed death ligand (PD-L) 1 and 2 on iNKT cells in protection against IAV remains to be elucidated. Here we investigated the effects of these co-stimulatory molecules on iNKT cells in the response to influenza. We discovered that compare to the wild type, PD-L1 deficient mice show reduced sensitivity to IAV infection as evident by reduced weight loss, decreased pulmonary inflammation and cellular infiltration. In contrast, PD-L2 deficient mice showed augmented weight loss, pulmonary inflammation and cellular infiltration compare to the wild type mice after influenza infection. Adoptive transfer of iNKT cells from wild type, PD-L1 or PD-L2 deficient mice into iNKT cell deficient mice recapitulated these findings. Interestingly, in our transfer system PD-L1−/−-derived iNKT cells produced high levels of interferon-gamma whereas PD-L2−/−-derived iNKT cells produced high amounts of interleukin-4 and 13 suggesting a role for these cytokines in sensitivity to influenza. We identified that PD-L1 negatively regulates the frequency of iNKT cell subsets in the lungs of IAV infected mice. Altogether, these results demonstrate that lack of PD-L1 expression by iNKT cells reduces the sensitivity to IAV and that the presence of PD-L2 is important for dampening the deleterious inflammatory responses after IAV infection. Our findings potentially have clinical implications for developing new therapies for influenza.
Collapse
|
|
38
|
Le Campion A, Larouche A, Fauteux-Daniel S, Soudeyns H. Pathogenesis of hepatitis C during pregnancy and childhood. Viruses 2012; 4:3531-50. [PMID: 23223189 PMCID: PMC3528278 DOI: 10.3390/v4123531] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Revised: 11/18/2012] [Accepted: 11/28/2012] [Indexed: 12/13/2022] Open
Abstract
The worldwide prevalence of HCV infection is between 1% and 8% in pregnant women and between 0.05% and 5% in children. Yet the pathogenesis of hepatitis C during pregnancy and in the neonatal period remains poorly understood. Mother-to-child transmission (MTCT), a leading cause of pediatric HCV infection, takes place at a rate of <10%. Factors that increase the risk of MTCT include high maternal HCV viral load and coinfection with HIV-1 but, intriguingly, not breastfeeding and mode of delivery. Pharmacological prevention of MTCT is not possible at the present time because both pegylated interferon alfa and ribavirin are contraindicated for use in pregnancy and during the neonatal period. However, this may change with the recent introduction of direct acting antiviral agents. This review summarizes what is currently known about HCV infection during pregnancy and childhood. Particular emphasis is placed on how pregnancy-associated immune modulation may influence the progression of HCV disease and impact MTCT, and on the differential evolution of perinatally acquired HCV infection in children. Taken together, these developments provide insights into the pathogenesis of hepatitis C and may inform strategies to prevent the transmission of HCV from mother to child.
Collapse
Affiliation(s)
- Armelle Le Campion
- Unité d’immunopathologie virale, Centre de recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, local 6735, Montreal, Quebec, H3T 1C5, Canada; E-Mails: (A.L.C); (A.L.); (S.F.-D.)
| | - Ariane Larouche
- Unité d’immunopathologie virale, Centre de recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, local 6735, Montreal, Quebec, H3T 1C5, Canada; E-Mails: (A.L.C); (A.L.); (S.F.-D.)
- Department of Microbiology & Immunology, Faculty of Medicine, Université de Montréal, C.P. 6128, Succ. Centre-ville, Montreal, Quebec, H3C 3J7, Canada
| | - Sébastien Fauteux-Daniel
- Unité d’immunopathologie virale, Centre de recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, local 6735, Montreal, Quebec, H3T 1C5, Canada; E-Mails: (A.L.C); (A.L.); (S.F.-D.)
- Department of Microbiology & Immunology, Faculty of Medicine, Université de Montréal, C.P. 6128, Succ. Centre-ville, Montreal, Quebec, H3C 3J7, Canada
| | - Hugo Soudeyns
- Unité d’immunopathologie virale, Centre de recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, local 6735, Montreal, Quebec, H3T 1C5, Canada; E-Mails: (A.L.C); (A.L.); (S.F.-D.)
- Department of Microbiology & Immunology, Faculty of Medicine, Université de Montréal, C.P. 6128, Succ. Centre-ville, Montreal, Quebec, H3C 3J7, Canada
- Department of Pediatrics, Faculty of Medicine, Université de Montréal, C.P. 6128, Succ. Centre-ville, Montreal, Quebec, H3C 3J7, Canada
| |
Collapse
|
|
39
|
Girardi E, Zajonc DM. Molecular basis of lipid antigen presentation by CD1d and recognition by natural killer T cells. Immunol Rev 2012; 250:167-79. [PMID: 23046129 PMCID: PMC3471380 DOI: 10.1111/j.1600-065x.2012.01166.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Together with peptides, T lymphocytes respond to hydrophobic molecules, mostly lipids, presented by the non-classical CD1 family (CD1a-e). These molecules have evolved complex and diverse binding grooves in order to survey different cellular compartments for self and exogenous antigens, which are then presented for recognition to T-cell receptors (TCRs) on the surface of T cells. In particular, most CD1d-presented antigens are recognized by a population of lymphocytes denominated natural killer T (NKT) cells, characterized by a strong immunomodulatory potential. Among NKT cells, two major subsets (type I and type II NKT cells) have been described, based on their TCR repertoire and antigen specificity. Here we review recent structural and biochemical studies that have shed light on the molecular details of CD1d-mediated antigen recognition by type I and II NKT cells, which are in many aspects distinct from what has been observed for peptide major histocompatibility complex-reactive TCRs.
Collapse
MESH Headings
- Animals
- Antigen-Presenting Cells/cytology
- Antigen-Presenting Cells/immunology
- Antigen-Presenting Cells/metabolism
- Antigens/chemistry
- Antigens/immunology
- Antigens/metabolism
- Antigens, CD1d/chemistry
- Antigens, CD1d/immunology
- Antigens, CD1d/metabolism
- Binding Sites
- Epitopes
- Humans
- Killer Cells, Natural/cytology
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Lipids/chemistry
- Lipids/immunology
- Mice
- Models, Molecular
- Protein Binding
- Protein Conformation
- Protein Multimerization
- Receptors, Antigen, T-Cell/chemistry
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/metabolism
Collapse
Affiliation(s)
- Enrico Girardi
- Division of Cell Biology, La Jolla Institute for Allergy and Immunology, CA, USA
| | | |
Collapse
|
|
40
|
Rhost S, Sedimbi S, Kadri N, Cardell SL. Immunomodulatory type II natural killer T lymphocytes in health and disease. Scand J Immunol 2012; 76:246-55. [PMID: 22724893 DOI: 10.1111/j.1365-3083.2012.02750.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Natural killer T (NKT) lymphocytes are αβ T cells activated by lipid-based ligands presented on the non-polymorphic CD1d-molecule. Type I NKT cells that carry an invariant Vα14 (in the mouse) or Vα24 (in humans) T cell receptor α-chain rearrangement have received significant attention for their involvement in a diversity of immune reactions. Their sister population, CD1d-restricted type II NKT cells, has been more difficult to study because of the lack of molecular markers that specify these cells. In the last few years, however, significant progress has been made, demonstrating that type II NKT cells have unique functions in immune responses to tumours and infections, in autoimmunity, obesity and graft-versus-host disease. Type II NKT cells appear more frequent than type I NKT cells in humans and accumulate in certain diseases such as ulcerative colitis, hepatitis and multiple myeloma. Recently, novel type II NKT cell ligands have been identified, and it is becoming clear that the type II NKT cell population may be oligoclonal. Here, we review the recent progress in the study of type II NKT cells, supporting the view that type II NKT cells may be attractive targets for immunotherapy.
Collapse
Affiliation(s)
- S Rhost
- Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | | | | | | |
Collapse
|
|
41
|
Kornek M, Lynch M, Mehta SH, Lai M, Exley M, Afdhal NH, Schuppan D. Circulating microparticles as disease-specific biomarkers of severity of inflammation in patients with hepatitis C or nonalcoholic steatohepatitis. Gastroenterology 2012; 143:448-58. [PMID: 22537612 PMCID: PMC3404266 DOI: 10.1053/j.gastro.2012.04.031] [Citation(s) in RCA: 162] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2011] [Revised: 03/26/2012] [Accepted: 04/09/2012] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Microparticles released into the bloodstream upon activation or apoptosis of CD4(+) and CD8(+) T cells correlate with inflammation as determined by histologic analysis in patients with chronic hepatitis C (CHC). Patients with nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH) can be differentiated from those with CHC based on activation of distinct sets of immune cells in the liver. METHODS We compared profiles of circulating microparticles from patients with NAFL and NASH (n = 67) to those of CHC (n = 42), with healthy individuals (controls) using flow cytometry; the profiles were correlated with inflammation grade and fibrosis stage based on histologic analyses. We assessed the ability of the profiles to determine the severity of inflammation and fibrosis based on serologic and histologic analyses. RESULTS Patients with CHC had increased levels of microparticles from CD4(+) and CD8(+) T cells; the levels correlated with disease severity based on histologic analysis and levels of alanine aminotransferase. Patients with NAFL or NASH had significant increases in numbers of microparticles from invariant natural killer T cells and macrophages/monocytes (CD14(+)), which mediate pathogenesis of NASH. Microparticles from CD14(+) and invariant natural killer T cells correlated with levels of alanine aminotransferase and severity of NASH (based on histology). Levels of microparticles could differentiate between patients with NAFL or NASH and those with CHC, or either group of patients and controls (area under the receiver operating characteristic curves ranging from 0.56 to 0.99). CONCLUSIONS Quantification of immune cell microparticles from serum samples can be used to assess the extent and characteristics of hepatic inflammation in patients with chronic liver disease.
Collapse
Affiliation(s)
- Miroslaw Kornek
- Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Michael Lynch
- Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | | | - Michelle Lai
- Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Mark Exley
- Cancer Biology Program, Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Nezam H. Afdhal
- Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Detlef Schuppan
- Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA,Division of Molecular and Translational Medicine, Dept. of Medicine I, Univ. of Mainz Medical School, Mainz, Germany
| |
Collapse
|
|
42
|
Liu Y, Munker S, Müllenbach R, Weng HL. IL-13 Signaling in Liver Fibrogenesis. Front Immunol 2012; 3:116. [PMID: 22593760 PMCID: PMC3349963 DOI: 10.3389/fimmu.2012.00116] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2012] [Accepted: 04/23/2012] [Indexed: 01/07/2023] Open
Abstract
Liver fibrosis is the final common pathway of chronic liver diseases irrespective of etiology. However, etiology deeply impacts progression and characteristics of liver fibrogenesis. IL-13 is the dominant pro-fibrotic cytokine in Schistosomiasis associated liver fibrogenesis. In vitro, IL-13 directly induces expression of fibrosis-associated genes, e.g., collagens or connective tissue growth factor, in hepatic stellate cells. Recently, potential effects of IL-13 in non-Schistosomiasis associated liver fibrosis have been uncovered. This review summarizes the potential roles of IL-13 in chronic liver disease of different etiologies, and the downstream events mediating IL-13 signaling in liver fibrogenesis.
Collapse
Affiliation(s)
- Yan Liu
- Molecular Hepatology - Alcohol Associated Diseases, II. Medical Clinic Faculty of Medicine at Mannheim, University of Heidelberg Mannheim, Germany
| | | | | | | |
Collapse
|
|
43
|
Role of NKT Cells in the Pathogenesis of NAFLD. Int J Hepatol 2012; 2012:850836. [PMID: 22577564 PMCID: PMC3335183 DOI: 10.1155/2012/850836] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2011] [Revised: 01/12/2012] [Accepted: 01/23/2012] [Indexed: 12/16/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease and shows various inflammatory changes in the liver. Among those inflammatory cells, natural killer T (NKT) cells are found to have a critical role during the disease progression. NKT cells may have a protective role at the early stage with simple steatosis through modification of insulin resistance, whereas they act as a progression factor at the advanced stage with fibrosis. Those processes are thought to depend on interaction between NKT cells and CD1d molecule in the liver.
Collapse
|
|
44
|
Jiang X, Zhang M, Lai Q, Huang X, Li Y, Sun J, Abbott WG, Ma S, Hou J. Restored circulating invariant NKT cells are associated with viral control in patients with chronic hepatitis B. PLoS One 2011; 6:e28871. [PMID: 22194934 PMCID: PMC3241692 DOI: 10.1371/journal.pone.0028871] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Accepted: 11/16/2011] [Indexed: 12/31/2022] Open
Abstract
Invariant NKT (iNKT) cells are involved in the pathogenesis of various infectious diseases. However, their role in hepatitis B virus (HBV) infection is not fully understood, especially in human species. In this study, 35 chronic hepatitis B (CHB) patients, 25 inactive carriers (IC) and 36 healthy controls (HC) were enrolled and the proportions of circulating iNKT cells in fresh isolated peripheral blood mononuclear cells (PBMC) were detected by flow cytometry. A longitudinal analysis was also conducted in 19 CHB patients who received antiviral therapy with telbivudine. Thereafter, the immune functions of iNKT cells were evaluated by cytokine secretion and a two-chamber technique. The median frequency of circulating iNKT cells in CHB patients (0.13%) was lower than that in HC (0.24%, P = 0.01) and IC (0.19%, P = 0.02), and increased significantly during antiviral therapy with telbivudine (P = 0.0176). The expressions of CC chemokine receptor 5 (CCR5) and CCR6 were dramatically higher on iNKT cells (82.83%±9.87%, 67.67%±16.83% respectively) than on conventional T cells (30.5%±5.65%, 14.02%±5.92%, both P<0.001) in CHB patients. Furthermore, iNKT cells could migrate toward the CC chemokine ligand 5. Patients with a high ratio (≥1.0) of CD4−/CD4+ iNKT cells at baseline had a higher rate (58.33%) of HBeAg seroconversion than those with a low ratio (<1.0, 0%, P = 0.0174). In conclusion, there is a low frequency of peripheral iNKT cells in CHB patients, which increases to normal levels with viral control. The ratio of CD4−/CD4+ iNKT cells at baseline may be a useful predictor for HBeAg seroconversion in CHB patients on telbivudine therapy.
Collapse
Affiliation(s)
- Xiaotao Jiang
- Institute of Hepatology and Key Lab for Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Department of Immunology, Basic Medicine School, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Mingxia Zhang
- Institute of Hepatology and Key Lab for Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Qintao Lai
- Institute of Hepatology and Key Lab for Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Xuan Huang
- Institute of Hepatology and Key Lab for Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Yongyin Li
- Institute of Hepatology and Key Lab for Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Jian Sun
- Institute of Hepatology and Key Lab for Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - William G.H. Abbott
- Institute of Hepatology and Key Lab for Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- The New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | - Shiwu Ma
- Institute of Hepatology and Key Lab for Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Jinlin Hou
- Institute of Hepatology and Key Lab for Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- * E-mail:
| |
Collapse
|
|
45
|
Petrovic D, Dempsey E, Doherty DG, Kelleher D, Long A. Hepatitis C virus--T-cell responses and viral escape mutations. Eur J Immunol 2011; 42:17-26. [PMID: 22125159 DOI: 10.1002/eji.201141593] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2011] [Revised: 07/15/2011] [Accepted: 10/05/2011] [Indexed: 01/25/2023]
Abstract
Hepatitis C virus (HCV) is a small, enveloped RNA virus and the number of HCV-infected individuals worldwide is estimated to be approximately 170 million. Most HCV infections persist, with up to 80% of all cases leading to chronic hepatitis associated with liver fibrosis, cirrhosis, and hepatocellular carcinoma. HCV-host interactions have a crucial role in viral survival, persistence, pathogenicity of infection, and disease progression. Maintenance of a vigorous, sustained cellular immune response recognizing multiple epitopes is essential for viral clearance. To escape immune surveillance, HCV alters its epitopes so that they are no-longer recognized by T cells and neutralizing antibodies, in addition to interfering with host cell cellular components and signaling pathways. The generation of escape variants is one of the most potent immune evasion strategies utilized by HCV. A large body of evidence suggests that single or multiple mutations within HLA-restricted epitopes contribute to viral immune escape and establishment of viral persistence. Further elucidation of the molecular mechanisms underlying immune escape will aid in the design of novel vaccines and therapeutics for the disease.
Collapse
Affiliation(s)
- Danijela Petrovic
- Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
| | | | | | | | | |
Collapse
|
|
46
|
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.
Collapse
Affiliation(s)
- Joelle Renneson
- Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; Université Lille Nord de France, Lille, France
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Exley MA, Lynch L, Varghese B, Nowak M, Alatrakchi N, Balk SP. Developing understanding of the roles of CD1d-restricted T cell subsets in cancer: reversing tumor-induced defects. Clin Immunol 2011; 140:184-95. [PMID: 21646050 PMCID: PMC3143311 DOI: 10.1016/j.clim.2011.04.017] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Revised: 04/20/2011] [Accepted: 04/21/2011] [Indexed: 12/22/2022]
Abstract
Invariant natural killer T-cells ('iNKT') are the best-known CD1d-restricted T-cells, with recently-defined roles in controlling adaptive immunity. CD1d-restricted T-cells can rapidly produce large amounts of Th1 and/or Th2//Treg/Th17-type cytokines, thereby regulating immunity. iNKT can stimulate potent anti-tumor immune responses via production of Th1 cytokines, direct cytotoxicity, and activation of effectors. However, Th2//Treg-type iNKT can inhibit anti-tumor activity. Furthermore, iNKT are decreased and/or reversibly functionally impaired in many advanced cancers. In some cases, CD1d-restricted T-cell cancer defects can be traced to CD1d(+) tumor interactions, since hematopoietic, prostate, and some other tumors can express CD1d. Ligand and IL-12 can reverse iNKT defects and therapeutic opportunities exist in correcting such defects alone and in combination. Early stage clinical trials have shown potential for reconstitution of iNKT IFN-gamma responses and evidence of activity in a subset of patients, with rational new approaches to capitalize on this progress ongoing, as will be discussed here.
Collapse
Affiliation(s)
- Mark A Exley
- Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
| | | | | | | | | | | |
Collapse
|
|
48
|
Batista VG, Moreira-Teixeira L, Leite-de-Moraes MC, Benard G. Analysis of invariant natural killer T cells in human paracoccidioidomycosis. Mycopathologia 2011; 172:357-63. [PMID: 21805204 DOI: 10.1007/s11046-011-9451-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2011] [Accepted: 07/12/2011] [Indexed: 12/28/2022]
Abstract
Invariant natural killer T (iNKT) cells are capable of recognizing lipid antigens and secreting Th1/Th2 cytokines. Deficiency in iNKT cell number or function has been partially implicated in susceptibility to some infectious diseases, such as tuberculosis. We evaluated iNKT cells in paracoccidioidomycosis, another chronic granulomatous disease endemic in Latin America. iNKT cells were detected using PBS57-loaded tetramer staining and flow cytometry. Circulating iNKT cell numbers were similar among healthy individuals who had previously been cured of paracoccidioidomycosis (susceptible individuals, n = 7) and healthy Paracoccidioides brasiliensis-infected (n = 5) and non-infected individuals (n = 5). iNKT from all three groups expanded similarly upon α-GalCer and a synthetic analog (OCH) stimulation. IFN-γ was the dominant cytokine produced both by ex vivo and by expanded iNKT cells, followed by IL-4 and IL-10, in the three groups. No deficit in the monocyte expression of CD1d was detected. In conclusion, individuals who had developed paracoccidioidomycosis in the past have no impairment in iNKT number, expansion capacity, and cytokine secretion.
Collapse
Affiliation(s)
- Vanessa Gomes Batista
- Laboratory of Medical Investigation Unit 53, Tropical Medicine Institute, University of São Paulo, Avenida Dr. Enéas de Carvalho Aguiar, 470. IMT-II, Térreo, São Paulo, SP, 05403-907, Brazil.
| | | | | | | |
Collapse
|
|
49
|
Lockridge JL, Chen X, Zhou Y, Rajesh D, Roenneburg DA, Hegde S, Gerdts S, Cheng TY, Anderson RJ, Painter GF, Moody DB, Burlingham WJ, Gumperz JE. Analysis of the CD1 antigen presenting system in humanized SCID mice. PLoS One 2011; 6:e21701. [PMID: 21738769 PMCID: PMC3128084 DOI: 10.1371/journal.pone.0021701] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2011] [Accepted: 06/05/2011] [Indexed: 11/18/2022] Open
Abstract
CD1 molecules are glycoproteins that present lipids and glycolipids for recognition by T cells. CD1-dependent immune activation has been implicated in a wide range of immune responses, however, our understanding of the role of this pathway in human disease remains limited because of species differences between humans and other mammals: whereas humans express five different CD1 gene products (CD1a, CD1b, CD1c, CD1d, and CD1e), muroid rodents express only one CD1 isoform (CD1d). Here we report that immune deficient mice engrafted with human fetal thymus, liver, and CD34(+) hematopoietic stem cells develop a functional human CD1 compartment. CD1a, b, c, and d isoforms were highly expressed by human thymocytes, and CD1a(+) cells with a dendritic morphology were present in the thymic medulla. CD1(+) cells were also detected in spleen, liver, and lungs. APCs from spleen and liver were capable of presenting bacterial glycolipids to human CD1-restricted T cells. ELISpot analyses of splenocytes demonstrated the presence of CD1-reactive IFN-γ producing cells. CD1d tetramer staining directly identified human iNKT cells in spleen and liver samples from engrafted mice, and injection of the glycolipid antigen α-GalCer resulted in rapid elevation of human IFN-γ and IL-4 levels in the blood indicating that the human iNKT cells are biologically active in vivo. Together, these results demonstrate that the human CD1 system is present and functionally competent in this humanized mouse model. Thus, this system provides a new opportunity to study the role of CD1-related immune activation in infections to human-specific pathogens.
Collapse
Affiliation(s)
- Jennifer L. Lockridge
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Xiuxu Chen
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Ying Zhou
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Deepika Rajesh
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Drew A. Roenneburg
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Subramanya Hegde
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Sarah Gerdts
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Tan-Yun Cheng
- Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, United States of America
| | - Regan J. Anderson
- Carbohydrate Chemistry Team, Industrial Research Ltd, Lower Hutt, New Zealand
| | - Gavin F. Painter
- Carbohydrate Chemistry Team, Industrial Research Ltd, Lower Hutt, New Zealand
| | - D. Branch Moody
- Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, United States of America
| | - William J. Burlingham
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Jenny E. Gumperz
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
- * E-mail:
| |
Collapse
|
|
50
|
Ishikawa S, Ikejima K, Yamagata H, Aoyama T, Kon K, Arai K, Takeda K, Watanabe S. CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice. J Hepatol 2011; 54:1195-1204. [PMID: 21145835 DOI: 10.1016/j.jhep.2010.08.022] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2010] [Revised: 08/15/2010] [Accepted: 08/23/2010] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Several lines of evidence suggest that innate immunity plays a key role in hepatic fibrogenesis. To clarify the role of natural killer (NK) T cells in hepatic inflammation and fibrogenesis, we here investigated xenobiotics-induced liver injury and subsequent fibrogenesis in mice lacking mature NKT cells caused by genetic disruption of the CD1d molecule. METHODS Male CD1d-knockout (KO) and wild-type (WT) mice were given repeated intraperitoneal injections of thioacetamide (TAA, 3times/week; 0.1-0.2mg/g BW) for up to 9 weeks, or a single intraperitoneal injection of CCl(4) (1 μl/g). Liver histology was evaluated, and expression levels of cytokines and matrix-related genes in the liver were quantitatively measured by real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS Mortality following repeated injections of TAA was prevented almost completely in CD1d-KO mice. TAA-induced inflammatory responses and hepatocellular damage were markedly ameliorated in CD1d-KO mice. TAA-induced expression of smooth muscle α-actin (SMA) and transforming growth factor (TGF)β1 mRNA in the liver were also prevented largely in CD1d-KO mice. In fact, CD1d-KO mice developed minimal hepatic fibrosis after 9-weeks of administration of TAA, which caused overt bridging fibrosis in WT mice. Indeed, TAA-induced increases in α1(I)procollagen (COL1A1) and tissue inhibitor of matrix metalloproteinase (TIMP)-1 mRNA were blunted significantly in CD1d-KO mice. Similarly, acute CCl(4)-induced hepatic injury and subsequent profibrogenic responses were also reduced significantly in CD1d-KO mice. CONCLUSIONS These findings clearly indicated that CD1d-restricted NKT cells contribute to xenobiotics-induced hepatic inflammation, hepatocellular damage, and subsequent profibrogenic responses in the liver.
Collapse
Affiliation(s)
- Sachiko Ishikawa
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | | | | | | | | | | | | | | |
Collapse
|