Publications by authors named "Benedikt Strunz"

18 Publications

  • Page 1 of 1

Natural killer cells in antiviral immunity.

Nat Rev Immunol 2021 Jun 11. Epub 2021 Jun 11.

Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Natural killer (NK) cells play an important role in innate immune responses to viral infections. Here, we review recent insights into the role of NK cells in viral infections, with particular emphasis on human studies. We first discuss NK cells in the context of acute viral infections, with flavivirus and influenza virus infections as examples. Questions related to activation of NK cells, homing to infected tissues and the role of tissue-resident NK cells in acute viral infections are also addressed. Next, we discuss NK cells in the context of chronic viral infections with hepatitis C virus and HIV-1. Also covered is the role of adaptive-like NK cell expansions as well as the appearance of CD56 NK cells in the course of chronic infection. Specific emphasis is then placed in viral infections in patients with primary immunodeficiencies affecting NK cells. Not least, studies in this area have revealed an important role for NK cells in controlling several herpesvirus infections. Finally, we address new data with respect to the activation of NK cells and NK cell function in humans infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) giving rise to coronavirus disease 2019 (COVID-19).
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http://dx.doi.org/10.1038/s41577-021-00558-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194386PMC
June 2021

The impact of hepatitis B surface antigen on natural killer cells in patients with chronic hepatitis B virus infection.

Liver Int 2021 Apr 1. Epub 2021 Apr 1.

Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.

Background & Aims: During chronic hepatitis B virus (HBV) infection, suppressed functionality of natural killer (NK) cells might contribute to HBV persistence but the underlying mechanisms remain elusive. A peculiar feature of HBV is the secretion of large amount of hepatitis B surface antigen (HBsAg). However, the effect of HBsAg quantities on NK cells is unclear. The aim was to determine the effects of HBsAg quantities on NK cell functionality in patients with chronic hepatitis B (CHB).

Methods: Eighty CHB patients were included and categorized into four groups based on their HBsAg levels. As a control, 30 healthy donors were enrolled. NK cell frequency, phenotype and function were assessed using flow cytometry and correlated with HBsAg levels and liver enzymes.

Results: Compared to the healthy controls, a reshaping of NK cell pool towards more CD56 NK cells was observed during CHB infection. Importantly, NK cells in patients with low HBsAg levels (<100 IU/mL) displayed an activated phenotype with increased expression of activation makers CD38, granzyme B and proliferation marker Ki-67 while presenting with defective functional responses (MIP-1β, CD107a) at the same time. Furthermore, NK cell activation was negatively correlated with patient HBsAg levels while NK function correlated with patient age.

Conclusions: The differential regulation of NK cell phenotype and function suggests that activation of NK cells in patients with low serum HBsAg levels may contribute to HBV clearance.
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http://dx.doi.org/10.1111/liv.14885DOI Listing
April 2021

Continuous human uterine NK cell differentiation in response to endometrial regeneration and pregnancy.

Sci Immunol 2021 Feb 19;6(56). Epub 2021 Feb 19.

Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Immune cell differentiation is critical for adequate tissue-specific immune responses to occur. Here, we studied differentiation of human uterine natural killer cells (uNK cells). These cells reside in a tissue undergoing constant regeneration and represent the major leukocyte population at the maternal-fetal interface. However, their physiological response during the menstrual cycle and in pregnancy remains elusive. By surface proteome and transcriptome analysis as well as using humanized mice, we identify a differentiation pathway of uNK cells in vitro and in vivo with sequential acquisition of killer cell immunoglobulin-like receptors and CD39. uNK cell differentiation occurred continuously in response to the endometrial regeneration and was driven by interleukin-15. Differentiated uNK cells displayed reduced proliferative capacity and immunomodulatory function including enhanced angiogenic capacity. By studying human uterus transplantation and monozygotic twins, we found that the uNK cell niche could be replenished from circulation and that it was under genetic control. Together, our study uncovers a continuous differentiation pathway of human NK cells in the uterus that is coupled to profound functional changes in response to local tissue regeneration and pregnancy.
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http://dx.doi.org/10.1126/sciimmunol.abb7800DOI Listing
February 2021

Long-lasting Imprint in the Soluble Inflammatory Milieu despite Early Treatment of Acute Symptomatic Hepatitis C.

J Infect Dis 2021 Jan 31. Epub 2021 Jan 31.

Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.

Background: Treatment with direct acting antivirals (DAAs) in patients with chronic hepatitis C infection leads to partial restoration of soluble inflammatory mediators (SIMs). In contrast, we hypothesized that early DAA treatment of acute hepatitis C with DAAs may normalize most SIMs.

Methods: In this study, we made use of a unique cohort of acute symptomatic hepatitis C who cleared HCV with a 6-week course of ledipasvir/sofosbuvir. Plasma samples were used for proximity extension assay (PEA) measuring 92 proteins.

Results: Profound SIM alterations were observed in acute HCV patients, with marked upregulation of IL-6 and CXCL10 while certain mediators were down-regulated (e.g. MCP-4, IL-7). During treatment and follow-up, the majority of SIMs decreased but not all normalized (e.g. CDCP1, IL-18). Of note, SIMs that were down-regulated before DAA treatment remained suppressed while others that were initially unchanged, declined to lower values during treatment and follow-up (e.g.CD244).

Conclusions: Acute hepatitis C was associated with marked changes in the soluble inflammatory milieu as compared to both chronic hepatitis patients and healthy controls. Whereas early DAA treatment partly normalized this altered signature, long-lasting imprints of HCV remained. Thus, acute HCV-induced changes in the immune system may persist even after a short duration of viremia.
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http://dx.doi.org/10.1093/infdis/jiab048DOI Listing
January 2021

Reversal of Immunity After Clearance of Chronic HCV Infection-All Reset?

Front Immunol 2020 8;11:571166. Epub 2020 Oct 8.

Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Chronic viral infections cause deterioration of our immune system. However, since persistent infections rarely can be eliminated, the reinvigoration capacity of an exhausted immune system has remained largely elusive. Chronic hepatitis C virus (HCV) infection can since some years be effectively cured with novel direct acting antiviral agents. Thus, it is now possible to study reversal of immunity in patients that are cured from a long-lasting chronic infection. We here highlight recent developments in the analysis of various immune cell populations during and after clearance of HCV infection. Surprisingly, whereas reinvigoration of certain immune traits clearly can be seen, many features of immune exhaustion persist over time after viral elimination. Thus, a long-term chronic insult might result in irreversible damage to our immune system. This will be important to consider in therapeutic vaccination efforts against chronic infection and in the development of immunotherapy based strategies against cancer.
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http://dx.doi.org/10.3389/fimmu.2020.571166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578424PMC
May 2021

The cytokine profile of menstrual blood.

Acta Obstet Gynecol Scand 2021 02 24;100(2):339-346. Epub 2020 Sep 24.

Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.

Introduction: The menstrual cycle is regulated by a complex interplay between endometrial epithelial cells, endothelial cells, immune cells, and sex hormones. To communicate, cells secrete cytokines that have multiple and diverse effects on recipient cells. Knowledge of how these cells interact in the uterus is insufficient. Menstrual blood is easily accessible and provides a source to study menstrual cycle physiology. This study aimed to determine the cytokine profile in menstrual blood plasma and investigate the differences in cytokine profiles between menstrual and peripheral blood plasma. Several previous studies indicate an improved chance of embryo implantation after endometrial scratching. Consequently, our secondary aim was to compare the menstrual blood cytokine profile before and after luteal phase endometrial scratching.

Material And Methods: Nineteen healthy donors collected menstrual blood for the first 24 hours of menstruation in two sequential cycles. Matched peripheral blood was taken at the same time. An endometrial biopsy was performed at cycle day 7-9 post ovulation in between the two collection times. A Luminex multiplex assay was performed in one batch analyzing a predetermined group of cytokines in plasma.

Results: Peripheral blood plasma and menstrual blood plasma showed substantial significant differences in cytokine profile. In menstrual blood plasma, C5/C5a, interleukin-6 (IL-6), IL-1β, and CXCL8 were detected in high concentrations, whereas IL-2, IL-12p70, XCL1/Lymphotactin, and interferon-γ were low. The most pronounced median differences between menstrual and peripheral blood plasma were found for IL-6, IL-1β, and CXCL8. The cytokine profiles of menstrual blood plasma were similar between the individual donors and did not differ over two subsequent cycles. None of the cytokines analyzed in menstrual blood plasma differed significantly before or after luteal phase endometrial scratching (P < .01).

Conclusions: Our results demonstrate that the menstrual blood cytokine profile is distinctly different from peripheral blood plasma and that the inter-individual difference in menstrual blood cytokine profile in healthy donors is limited and stable over time. The small injury caused by an endometrial biopsy does not change the cytokine profile in the subsequent menstrual cycle. Our study provides new insights into menstrual cycle physiology.
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http://dx.doi.org/10.1111/aogs.13990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891423PMC
February 2021

Natural killer cell immunotypes related to COVID-19 disease severity.

Sci Immunol 2020 08;5(50)

Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Understanding innate immune responses in COVID-19 is important to decipher mechanisms of host responses and interpret disease pathogenesis. Natural killer (NK) cells are innate effector lymphocytes that respond to acute viral infections but might also contribute to immunopathology. Using 28-color flow cytometry, we here reveal strong NK cell activation across distinct subsets in peripheral blood of COVID-19 patients. This pattern was mirrored in scRNA-seq signatures of NK cells in bronchoalveolar lavage from COVID-19 patients. Unsupervised high-dimensional analysis of peripheral blood NK cells furthermore identified distinct NK cell immunotypes that were linked to disease severity. Hallmarks of these immunotypes were high expression of perforin, NKG2C, and Ksp37, reflecting increased presence of adaptive NK cells in circulation of patients with severe disease. Finally, arming of CD56 NK cells was observed across COVID-19 disease states, driven by a defined protein-protein interaction network of inflammatory soluble factors. This study provides a detailed map of the NK cell activation landscape in COVID-19 disease.
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http://dx.doi.org/10.1126/sciimmunol.abd6832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665314PMC
August 2020

Human endometrial MAIT cells are transiently tissue resident and respond to Neisseria gonorrhoeae.

Mucosal Immunol 2021 03 5;14(2):357-365. Epub 2020 Aug 5.

Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Mucosa-associated invariant T (MAIT) cells are non-classical T cells important in the mucosal defense against microbes. Despite an increasing interest in the immunobiology of the endometrial mucosa, little is known regarding human MAIT cells in this compartment. The potential role of MAIT cells as a tissue-resident local defense against microbes in the endometrium is largely unexplored. Here, we performed a high-dimensional flow cytometry characterization of MAIT cells in endometrium from pre- and postmenopausal women, and in decidua from first-trimester pregnancies. Furthermore, we assessed MAIT cell function by stimulation with Neisseria gonorrhoeae (N. gonorrhoeae). Endometrial MAIT (eMAIT) cells represented a stable endometrial immune cell population as limited dynamic changes were observed during the menstrual cycle, post menopause, or in response to pregnancy. Furthermore, eMAIT cells exhibited an activated tissue-resident phenotype. Despite expressing CD69 and CD103, eMAIT cells were replenished over time by circulating MAIT cells, as assessed using human uterus transplantation as a model. Finally, functional experiments revealed the capability of MAIT cells to respond to the sexually transmitted and tissue-relevant pathogen, N. gonorrhoeae. In conclusion, our study provides novel insight into human MAIT cell dynamics and anti-microbial properties in the human uterus.
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http://dx.doi.org/10.1038/s41385-020-0331-5DOI Listing
March 2021

Evidence for B cell maturation but not trained immunity in uninfected infants exposed to hepatitis C virus.

Gut 2020 12 27;69(12):2203-2213. Epub 2020 Apr 27.

Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

Objectives: Vertical transmission of hepatitis C virus (HCV) is rare compared with other chronic viral infections, despite that newborns have an immature, and possibly more susceptible, immune system. It further remains unclear to what extent prenatal and perinatal exposure to HCV affects immune system development in neonates.

Design: To address this, we studied B cells, innate immune cells and soluble factors in a cohort of 62 children that were either unexposed, exposed uninfected or infected with HCV. Forty of these infants were followed longitudinally from birth up until 18 months of age.

Results: As expected, evidence for B cell maturation was observed with increased age in children, whereas few age-related changes were noticed among innate immune cells. HCV-infected children had a high frequency of HCV-specific IgG-secreting B cells. Such a response was also detected in some exposed but uninfected children but not in uninfected controls. Consistent with this, both HCV-exposed uninfected and HCV-infected infants had evidence of early B cell immune maturation with an increased proportion of IgA-positive plasma cells and upregulated CD40 expression. In contrast, actual HCV viraemia, but not mere exposure, led to alterations within myeloid immune cell populations, natural killer (NK) cells and a distinct soluble factor profile with increased levels of inflammatory cytokines and chemokines.

Conclusion: Our data reveal that exposure to, and infection with, HCV causes disparate effects on adaptive B cells and innate immune cell such as myeloid cells and NK cells in infants.
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http://dx.doi.org/10.1136/gutjnl-2019-320269DOI Listing
December 2020

Plasma FABP4 is associated with liver disease recovery during treatment-induced clearance of chronic HCV infection.

Sci Rep 2020 02 7;10(1):2081. Epub 2020 Feb 7.

Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.

Direct-acting antivirals (DAAs) have dramatically improved the management of chronic hepatitis C (CHC). In this study, we investigated the effects of hepatitis C virus clearance on markers of systemic inflammation measured in plasma samples from CHC patients before, during and after DAA therapy. We identified a plasma soluble protein profile associated with CHC. Successful DAA therapy rapidly normalised the plasma inflammatory milieu, with the notable exception of soluble (s)CD163, a marker of macrophage activation, which remained elevated after viral clearance and segregated patients with high and low levels of cirrhosis. Patients who received DAA in combination with Ribavirin maintained elevated levels of CXCL10, consistent with an immune-stimulatory role of Ribavirin. As anticipated, DAA-treated patients experienced durable improvement in liver fibrosis measurements. Interestingly, pre-treatment levels of fatty acid-binding protein 4 (FABP4) were inversely associated with reduction of APRI and FIB-4 scores during treatment. Together, these results support the notion of a rapid restoration of many aspects of the inflammatory state in CHC patients in response to DAA therapy. Furthermore, the associations with sCD163 and FABP4 warrant further investigation into the role of macrophages in residual liver disease and fibrosis resolution after viral clearance.
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http://dx.doi.org/10.1038/s41598-020-58768-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005788PMC
February 2020

MAIT Cells Are Enriched and Highly Functional in Ascites of Patients With Decompensated Liver Cirrhosis.

Hepatology 2020 10 13;72(4):1378-1393. Epub 2020 Oct 13.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Background And Aims: Patients with advanced liver cirrhosis have an increased susceptibility to infections. As part of the cirrhosis-associated immune dysfunction, mucosal-associated invariant T (MAIT) cells, which have the capacity to respond to bacteria, are severely diminished in circulation and liver tissue. However, MAIT cell presence and function in the peritoneal cavity, a common anatomical site for infections in cirrhosis, remain elusive. In this study, we deliver a comprehensive investigation of the immune compartment present in ascites of patients with decompensated liver cirrhosis, and focus especially on MAIT cells.

Approach And Results: To study this, matched peripheral blood and ascites fluid were collected from 35 patients with decompensated cirrhosis, with or without spontaneous bacterial peritonitis (SBP). MAIT cell phenotype and function were analyzed using high-dimensional flow cytometry, and the obtained data were compared with the blood samples of healthy controls (n = 24) and patients with compensated cirrhosis (n = 11). We found circulating MAIT cells to be severely decreased in patients with cirrhosis as compared with controls. In contrast, in ascites fluid, MAIT cells were significantly increased together with CD14 CD16 monocytes, innate lymphoid cells, and natural killer cells. This was paralleled by elevated levels of several pro-inflammatory cytokines and chemokines in ascites fluid as compared with plasma. Peritoneal MAIT cells displayed an activated tissue-resident phenotype, and this was corroborated by increased functional responses following stimulation with E. coli or interleukin (lL)-12 + IL-18 as compared with circulating MAIT cells. During SBP, peritoneal MAIT cell frequencies increased most among all major immune cell subsets, suggestive of active homing of MAIT cells to the site of infection.

Conclusions: Despite severely diminished MAIT cell numbers and impaired phenotype in circulation, peritoneal MAIT cells remain abundant, activated, and highly functional in decompensated cirrhosis and are further enriched in SBP. This suggests that peritoneal MAIT cells could be of interest for immune-intervention strategies in patients with decompensated liver cirrhosis and SBP.
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http://dx.doi.org/10.1002/hep.31153DOI Listing
October 2020

29-Color Flow Cytometry: Unraveling Human Liver NK Cell Repertoire Diversity.

Front Immunol 2019 19;10:2692. Epub 2019 Nov 19.

Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.

Recent studies have demonstrated extraordinary diversity in peripheral blood human natural killer (NK) cells and have suggested environmental control of receptor expression patterns on distinct subsets of NK cells. However, tissue localization may influence NK cell differentiation to an even higher extent and less is known about the receptor repertoire of human tissue-resident NK cells. Advances in single-cell technologies have allowed higher resolution studies of these cells. Here, the power of high-dimensional flow cytometry was harnessed to unravel the complexity of NK cell repertoire diversity in liver since recent studies had indicated high heterogeneity within liver NK cells. A 29-color flow cytometry panel allowing simultaneous measurement of surface tissue-residency markers, activating and inhibitory receptors, differentiation markers, chemokine receptors, and transcription factors was established. This panel was applied to lymphocytes across three tissues (liver, peripheral blood, and tonsil) with different distribution of distinct NK cell subsets. Dimensionality reduction of this data ordered events according to their lineage, rather than tissue of origin. Notably, narrowing the scope of the analysis to the NK cell lineage in liver and peripheral blood separated subsets according to tissue, enabling phenotypic characterization of NK cell subpopulations in individual tissues. Such dimensionality reduction, coupled with a clustering algorithm, identified CD49e as the preferred marker for future studies of liver-resident NK cell subsets. We present a robust approach for diversity profiling of tissue-resident NK cells that can be applied in various homeostatic and pathological conditions such as reproduction, infection, and cancer.
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http://dx.doi.org/10.3389/fimmu.2019.02692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878906PMC
November 2020

Methods for High-Dimensional Flow Cytometry Analysis of Human MAIT Cells in Tissues and Peripheral Blood.

Methods Mol Biol 2020 ;2098:71-82

Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

Mucosal-associated invariant T (MAIT) cells can be found throughout the human body, in peripheral blood, at mucosal sites, and, among other organs, in the liver. As unconventional T cells, MAIT cells have the capacity to readily respond to bacterial infections and are also engaged during anti-viral responses. To thoroughly investigate the MAIT cell phenotype and function in such conditions, multi-color flow cytometry is an appropriate and powerful tool. Yet, the recent rapid technological development within this methodology, with generation of highly complex data, has increased the need for downstream dimensionality reducing methods to fully interpret obtained results. Among such methods, stochastic neighbor embedding (SNE) analysis stands out as it provides intuitive low-dimensional representations of complex data. Here, we describe techniques and workflow for high-dimensional state-of-the-art investigation and analysis of human MAIT cells from blood and peripheral tissues.
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http://dx.doi.org/10.1007/978-1-0716-0207-2_5DOI Listing
January 2021

Irreversible impact of chronic hepatitis C virus infection on human natural killer cell diversity.

Cell Stress 2018 Jul 25;2(8):216-218. Epub 2018 Jul 25.

Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.

Diversity is crucial for the immune system to efficiently combat infections. Natural killer (NK) cells are innate cytotoxic lymphocytes that contribute to the control of viral infections. NK cells were for long thought to be a homogeneous population of cells. However, recent work has instead revealed NK cells to represent a highly diverse population of immune cells where a vast number of subpopulations with distinct characteristics exist across tissues. However, the degree to which a chronic viral infection affects NK cell diversity remains elusive. Hepatitis C virus (HCV) is effective in establishing chronic infection in humans. During the last years, new direct-acting antiviral drugs (DAA) have revolutionized treatment of chronic hepatitis C, enabling rapid cure in the majority of patients. This allows us to study the influence of a chronic viral infection and its subsequent elimination on the NK cell compartment with a focus on NK cell diversity. In our recent study (Nat Commun, 9:2275), we show that chronic HCV infection irreversibly impacts human NK cell repertoire diversity.
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http://dx.doi.org/10.15698/cst2018.07.150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551629PMC
July 2018

Chronic hepatitis C virus infection irreversibly impacts human natural killer cell repertoire diversity.

Nat Commun 2018 06 11;9(1):2275. Epub 2018 Jun 11.

Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186, Stockholm, Sweden.

Diversity is a central requirement for the immune system's capacity to adequately clear a variety of different infections. As such, natural killer (NK) cells represent a highly diverse population of innate lymphocytes important in the early response against viruses. Yet, the extent to which a chronic pathogen affects NK cell diversity is largely unknown. Here we study NK cell functional diversification in chronic hepatitis C virus (HCV) infection. High-dimensional flow cytometer assays combined with stochastic neighbor embedding analysis reveal that chronic HCV infection induces functional imprinting on human NK cells that is largely irreversible and persists long after successful interventional clearance of the virus. Furthermore, HCV infection increases inter-individual, but decreases intra-individual, NK cell diversity. Taken together, our results provide insights into how the history of infections affects human NK cell diversity.
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http://dx.doi.org/10.1038/s41467-018-04685-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995831PMC
June 2018

IL13Rα2 expression identifies tissue-resident IL-22-producing PLZF innate T cells in the human liver.

Eur J Immunol 2018 08 25;48(8):1329-1335. Epub 2018 May 25.

Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

Innate lymphocytes are selectively enriched in the liver where they have important roles in liver immunology. Murine studies have shown that type I NKT cells can promote liver inflammation, whereas type II NKT cells have an anti-inflammatory role. In humans, type II NKT cells were found to accumulate in the gut during inflammation and IL13Rα2 was proposed as a marker for these cells. In the human liver, less is known about type I and II NKT cells. Here, we studied the phenotype and function of human liver T cells expressing IL13Rα2. We found that IL13Rα2 was expressed by around 1% of liver-resident memory T cells but not on circulating T cells. In support of their innate-like T-cell character, the IL13Rα2 T cells had higher expression of promyelocytic leukaemia zinc finger (PLZF) compared to IL13Rα2 T cells and possessed the capacity to produce IL-22. However, only a minority of human liver sulfatide-reactive type II NKT cells expressed IL13Rα2. Collectively, these findings suggest that IL13Rα2 identifies tissue-resident intrahepatic T cells with innate characteristics and the capacity to produce IL-22.
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http://dx.doi.org/10.1002/eji.201747334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733416PMC
August 2018

The novel deubiquitinase inhibitor b-AP15 induces direct and NK cell-mediated antitumor effects in human mantle cell lymphoma.

Cancer Immunol Immunother 2018 06 19;67(6):935-947. Epub 2018 Mar 19.

Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner site Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.

The first therapeutic proteasome inhibitor bortezomib has clinical efficacy in mantle cell lymphoma (MCL) which resulted in its incorporation in treatment algorithms for this disease. Impairment of proteasomal function by bortezomib is mediated via inhibition of the 20S core particle. However, proteasome function can also be modified by targeting upstream components of the ubiquitin-proteasome system. Recently, b-AP15 has been identified as a small molecule achieving proteasome inhibition by targeting the deubiquitinase (DUB) activity of the 19S regulatory subunit and was found to inhibit cancer cell growth in preclinical analyses. In the present study, both direct antitumor effects and the possibility to induce natural killer group 2 member D ligands (NKG2DL) to reinforce NK cell immunity with b-AP15 were investigated to provide a rational basis for clinical evaluation of this novel DUB inhibitor in MCL. Treatment with b-AP15 resulted in reduced viability as well as induction of apoptosis in a time- and dose-dependent manner, which could be attributed to caspase activation in MCL cells. In addition, treatment with b-AP15 differentially induced NKG2DL expression and subsequent NK cell lysis of MCL cells. These results indicate that the DUB inhibitor b-AP15 displays substantial antitumor activity in human MCL and suggest that b-AP15 might be a novel therapeutic option in the treatment of MCL that warrants clinical investigation.
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http://dx.doi.org/10.1007/s00262-018-2151-yDOI Listing
June 2018

Nonreversible MAIT cell-dysfunction in chronic hepatitis C virus infection despite successful interferon-free therapy.

Eur J Immunol 2016 09 12;46(9):2204-10. Epub 2016 Jul 12.

Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Immune exhaustion is a hallmark of chronic viral infections. However, pathogen eradication can result in reinvigorated immune responses. Indeed, this was recently suggested for antigen-specific CD8(+) T cells and NK cells in HCV-infected patients receiving an interferon-free treatment regimen. Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved innate-like effector T cells. Here, we show that MAIT cells are severely diminished in frequency in chronic HCV-infection, and in this regard the most affected immune cell type in peripheral blood of humans with this disease. Residual MAIT cells show an activated phenotype with high expression of granzyme B, HLA-DR, PD-1, and CD69 as well as altered transcription factor expression and suppressed responsiveness to MR1-dependent antigen stimulation. In contrast to other immune cells, MAIT cells are not reinvigorated after successful HCV-clearance using interferon-free therapy. The present results hence demonstrate persistent immune cell-dysfunction in humans despite successful elimination of a chronic pathogen.
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http://dx.doi.org/10.1002/eji.201646447DOI Listing
September 2016
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