Karl-Johan Malmberg

University of Oslo, Kristiania (historical), Oslo, Norway

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Publications (55)415.45 Total impact

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    ABSTRACT: The functional capacity of NK cells is dynamically tuned by integrated signals from inhibitory and activating cell surface receptors in a process termed NK cell education. However, the understanding of the cellular and molecular mechanisms behind this functional tuning is limited. In this study, we show that the expression of the adhesion molecule and activation receptor DNAX accessory molecule 1 (DNAM-1) correlates with the quantity and quality of the inhibitory input by HLA class I-specific killer cell Ig-like receptors and CD94/NKG2A as well as with the magnitude of functional responses. Upon target cell recognition, the conformational state of LFA-1 changed in educated NK cells, associated with rapid colocalization of both active LFA-1 and DNAM-1 at the immune synapse. Thus, the coordinated expression of LFA-1 and DNAM-1 is a central component of NK cell education and provides a potential mechanism for controlling cytotoxicity by functionally mature NK cells. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 03/2015; DOI:10.4049/jimmunol.1401972 · 5.36 Impact Factor
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    ABSTRACT: The mechanisms underlying human natural killer (NK) cell phenotypic and functional heterogeneity are unknown. Here, we describe the emergence of diverse subsets of human NK cells selectively lacking expression of signaling proteins after human cytomegalovirus (HCMV) infection. The absence of B and myeloid cell-related signaling protein expression in these NK cell subsets correlated with promoter DNA hypermethylation. Genome-wide DNA methylation patterns were strikingly similar between HCMV-associated adaptive NK cells and cytotoxic effector T cells but differed from those of canonical NK cells. Functional interrogation demonstrated altered cytokine responsiveness in adaptive NK cells that was linked to reduced expression of the transcription factor PLZF. Furthermore, subsets of adaptive NK cells demonstrated significantly reduced functional responses to activated autologous T cells. The present results uncover a spectrum of epigenetically unique adaptive NK cell subsets that diversify in response to viral infection and have distinct functional capabilities compared to canonical NK cell subsets. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 03/2015; 42(3):443-56. DOI:10.1016/j.immuni.2015.02.008 · 19.75 Impact Factor
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    ABSTRACT: A growing body of evidence suggests that the human natural killer (NK) cell compartment is phenotypically and functionally heterogeneous and composed of several differentiation stages. Moreover, NK cell subsets have recently been shown to exhibit adaptive immune features during herpesvirus infection in experimental mice and to preferentially expand during viral infections in humans. However, both phenotype and role of NK cells during acute symptomatic Epstein-Barr virus (EBV) infection, termed infectious mononucleosis (IM), remain unclear. Here, we longitudinally assessed the kinetics, the differentiation and the proliferation of subsets of NK cells in pediatric IM patients. Our results indicate that acute IM is characterized by the preferential proliferation of early-differentiated CD56(dim) NKG2A(+) KIR(-) NK cells. Moreover, this NK cell subset exhibits features of terminal differentiation and persists at higher frequency over at least the first 6 months after acute IM. Finally, we demonstrate that this NK cell subset preferentially degranulates and proliferates upon exposure to EBV-infected B cells expressing lytic antigens. Thus, early-differentiated NK cells might play a key role in the immune control of primary infection with this persistent tumor-associated virus.
    Blood 09/2014; DOI:10.1182/blood-2014-01-553024 · 9.78 Impact Factor
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    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) is widely used to treat hematopoietic cell disorders, but is often complicated by graft versus host disease (GvHD) that causes severe epithelial damage. Here we have investigated longitudinally the effects of induction chemotherapy, conditioning radio-chemotherapy and allogeneic HSCT on composition, phenotype and recovery of circulating innate lymphoid cells (ILC) in 51 acute leukemia patients. We found that reconstitution of ILC1, ILC2 and NCR(-) ILC3 was slow compared to that of neutrophils and monocytes. NCR(+) ILC3 which are not present in the circulation of healthy individuals appeared both after induction chemotherapy and after allogeneic HSCT. Circulating patient ILC before transplantation as well as donor ILC after transplantation expressed activation (CD69), proliferation (Ki-67) and tissue homing markers for gut (α4β7, CCR6) and skin (CCR10 and CLA). The proportion ILC expressing these markers was associated with a decreased susceptibility to therapy-induced mucositis and acute GvHD. Taken together, these data suggest that ILC recovery and treatment-related tissue damage are interrelated and affect the development of GvHD.
    Blood 05/2014; 124(5). DOI:10.1182/blood-2013-11-536888 · 9.78 Impact Factor
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    ABSTRACT: Although hepatitis delta is considered an immune-mediated disease, adaptive immune responses to hepatitis delta virus (HDV) are hardly detectable. Thus, the role of other immune responses, including those mediated by natural killer (NK) cells, must be considered in HDV pathogenesis and in treatments with immune-stimulating agents such as interferon (IFN)α. However, the phenotype and function of NK cells in chronic HDV infection, or in HDV-infected individuals undergoing IFNα treatment, have not been extensively studied. We performed an extensive analysis of NK cells in chronically HDV-infected patients before and during treatment with IFNα, and compared the results with those for patients with HBV mono-infection as well as healthy controls. In untreated HDV-infected patients, a higher than normal frequency of NK cells was observed in peripheral blood with unaltered phenotypic NK cell differentiation status. In contrast, long-term IFNα treatment of HDV-infected patients caused a significant change in NK cell differentiation status, with selective loss of terminally differentiated NK cells and, in parallel, a relative enrichment in immature NK cell subsets. Treatment was associated with marked functional impairment of the NK cells, which was independent of the changes in NK cell differentiation status. Furthermore, treatment polarised NK cell IFN signalling from STAT4 towards STAT1 dependency. Strikingly, a high frequency of CD56(dim) NK cells at baseline was positively associated with IFNα treatment outcome in the patients. We describe in detail how HDV infection, and IFNα treatment of this infection, affects the NK cell compartment and what consequences this has for the functional capacity of NK cells.
    Gut 04/2014; 64(3). DOI:10.1136/gutjnl-2014-306767 · 13.32 Impact Factor
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    ABSTRACT: Natural killer (NK) cells are functionally tuned by education via killer cell immunoglobulin receptors (KIRs) interacting with HLA class I molecules. We examined the effect of KIR gene copy number variation (CNV) on the education of human NK cells. The frequency of NK cells expressing a given KIR correlated with the copy number of that gene. However, co-expression of multiple copies from a single locus, or duplicated loci, was infrequent, in line with independent transcriptional regulation of each allele or copy. Intriguingly, co-expression of two KIR alleles, resulting in higher surface expression, did not lead to enhanced functional responses in vitro or to selective advantages during in vivo responses to cytomegalovirus infection, suggesting that receptor density does not influence NK education at the single cell level. However, individuals with multiple KIR gene copies had higher frequencies of responding cells, consistent with heightened overall responsiveness.
    Blood 05/2013; DOI:10.1182/blood-2012-10-461442 · 9.78 Impact Factor
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    ABSTRACT: The Natural Killer (NK) cell population is composed of subsets of varying sizes expressing different combinations of inhibitory receptors for MHC class I molecules. Genes within the NK gene complex, including the inhibitory receptors themselves, seem to be the primary intrinsic regulators of inhibitory receptor expression, but the MHC class I background is an additional Modulating factor. In this paper, we have performed a parallel study of the inhibitory receptor repertoire in inbred mice of the C57Bl/6 background and in a cohort of 44 humans. Deviations of subset frequencies from the "product rule (PR)," i.e., differences between observed and expected frequencies of NK cells, were used to identify MHC-independent and MHC-dependent control of receptor expression frequencies. Some deviations from the PR were similar in mice and humans, such as the decreased presence of NK cell subset lacking inhibitory receptors. Others were different, including a role for NKG2A in determining over- or under-representation of specific subsets in humans but not in mice. Thus, while human and murine inhibitory receptor repertoires differed in details, there may also be shared principles governing NK cell repertoire formation in these two species.
    Frontiers in Immunology 03/2013; 4:65. DOI:10.3389/fimmu.2013.00065
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    ABSTRACT: Human NK cells are functionally regulated by killer cell immunoglobulin-like receptors (KIRs) and their interactions with HLA class I molecules. As KIR expression in a given NK cell is genetically hard-wired, we hypothesized that KIR repertoire perturbations reflect expansions of unique NK cell subsets and may be used to trace adaptation of the NK cell compartment to viral infections. By determining the human "KIR-ome" at a single cell level in over 200 donors, we were able to analyze the magnitude of NK cell adaptation to viral infections in healthy individuals. Strikingly, infection with human cytomegalovirus (CMV), but not with other common herpesviruses, induced expansion and differentiation of KIR-expressing NK cells, visible as stable imprints in the repertoire. Education by inhibitory KIRs promoted the clonal-like expansion of NK cells, causing a bias for self-specific inhibitory KIRs. Furthermore, our data revealed a unique contribution of activating KIRs (KIR2DS4, KIR2DS2, or KIR3DS1), in addition to NKG2C, in the expansion of human NK cells. These results provide new insight into KIR repertoire diversity and its adaptation to viral infection, suggesting a role for both activating and inhibitory KIRs in immunity to CMV infection.
    Blood 01/2013; 121(14). DOI:10.1182/blood-2012-10-459545 · 9.78 Impact Factor
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    ABSTRACT: Despite intense scrutiny of the molecular interactions between natural killer (NK) and target cells, few studies have been devoted to dissection of basic functional heterogeneity in individual NK cell behavior. By using a microchip-based, time-lapse imaging approach allowing the entire contact history of each NK cell to be recorded, we could quantify how the cytotoxic response varies between individual NK cells. Strikingly, about half of the NK cells did not kill any target cells at all, while a minority of NK cells was responsible for a majority of the target cell deaths. These dynamic cytotoxicity data allowed categorization of NK cells into five distinct classes. A small but particularly active sub-class of NK cells killed several target cells in a consecutive fashion. These 'serial killers' delivered their lytic hits faster and induced faster target cell death than other NK cells. Fast, necrotic target cell death was correlated with the amount of perforin released by the NK cells. Our data are consistent with a model where a small fraction of NK cells drives tumor elimination and inflammation.
    Blood 01/2013; 121(8). DOI:10.1182/blood-2012-06-439851 · 9.78 Impact Factor
  • Karl-Johan Malmberg
    Blood 12/2012; 120(24):4663-4. DOI:10.1182/blood-2012-09-457184 · 9.78 Impact Factor
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    Karl-Johan Malmberg, Vivien Beziat, Hans-Gustaf Ljunggren
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    ABSTRACT: Immune responses to cytomegalovirus (CMV) infection in the mouse and human involve the expansion of specific subsets of natural killer (NK) cells with specific phenotypic characteristics and a heightened ability to produce interferon (IFN)-gamma. In humans, these NK-cell responses are largely driven by the activating receptor NKG2C, which recognize human leukocyte antigen (HLA)-E in complex with leader sequence peptides. In this issue of the European Journal of Immunology, Noyola et al. [Eur. J. Immunol. 2012, 42: 3256-3266] examine NK-cell responses in a unique cohort of young children with asymptomatic and symptomatic congenital CMV infection. They also address NK-cell responses to CMV in relation to NKG2C gene copy number. Children with a symptomatic congenital infection exhibited a marked expansion of NKG2C(+) NK cells. However, despite having slightly lower frequencies of NKG2C(+) NK cells, children with a heterozygous deletion of the NKG2C gene seemed to control the virus as efficiently as those with two copies of the NKG2C gene. The present studies shed new light on the role of NKG2C copy number variation on the human NK-cell response to CMV infection.
    European Journal of Immunology 12/2012; 42(12):3141-5. DOI:10.1002/eji.201243050 · 4.52 Impact Factor
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    ABSTRACT: Epistatic interactions between killer cell immunoglobulin-like receptors (KIRs) and their cognate HLA class I ligands have important implications for reproductive success, antiviral immunity, susceptibility to autoimmune conditions and cancer, as well as for graft-versus-leukemia reactions in settings of allogeneic stem cell transplantation. Although CD8 T cells are known to acquire KIRs when maturing from naive to terminally differentiated cells, little information is available about the constitution of KIR repertoires on human CD8 T cells. Here, we have performed a high-resolution analysis of KIR expression on CD8 T cells. The results show that most CD8 T cells possess a restricted KIR expression pattern, often dominated by a single activating or inhibitory KIR. Furthermore, the expression of KIR, and its modulation of CD8 T-cell function, was independent of expression of self-HLA class I ligands. Finally, despite similarities in the stochastic regulation of KIRs by the bidirectional proximal promoter, the specificity of inhibitory KIRs on CD8 T cells was often distinct from that of natural killer cells in the same individual. The results provide new insight into the formation of KIR repertoires on human T cells.
    Blood 09/2012; 120(17):3455-65. DOI:10.1182/blood-2012-03-416867 · 9.78 Impact Factor
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    ABSTRACT: Natural killer (NK) cells are affected by infection with human cytomegalovirus (HCMV) manifested by increased expression of the HLA-E binding activating receptor NKG2C. We here show that HCMV seropositivity was associated with a profound expansion of NKG2C(+) CD56(dim) NK cells in patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Multi-color flow cytometry revealed that the expanded NKG2C(+) CD56(dim) NK cells displayed a highly differentiated phenotype, expressed high amounts of granzyme B and exhibited polyfunctional responses (CD107a, IFN-γ, and TNF-α) to stimulation with antibody-coated as well as HLA-E expressing target cells but not when stimulated with IL-12/IL-18. More importantly, NKG2C(+) CD56(dim) NK cells had a clonal expression pattern of inhibitory killer cell immunoglobulin-like receptors (KIRs) specific for self-HLA class I molecules, with predominant usage of KIR2DL2/3. KIR engagement dampened NKG2C-mediated activation suggesting that such biased expression of self-specific KIRs may preserve self-tolerance and limit immune-pathology during viral infection. Together, these findings shed new light on how the human NK-cell compartment adjusts to HCMV infection resulting in clonal expansion and differentiation of educated and polyfunctional NK cells.
    European Journal of Immunology 02/2012; 42(2):447-57. DOI:10.1002/eji.201141826 · 4.52 Impact Factor
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    ABSTRACT: The seventh killer cell immunoglobulin-like receptor (KIR) workshop was held at Tammsvik, Stockholm, Sweden, in the summer of 2011. This intimate and isolated setting brought together approximately 100 investigators, from a range of scientific disciplines, who are all actively working on KIRs in humans or closely related primate species.
    Immunity 11/2011; 35(5):653-7. DOI:10.1016/j.immuni.2011.11.007 · 19.75 Impact Factor
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    ABSTRACT: Human natural killer (NK) cell differentiation, characterized by a loss of NKG2A in parallel with the acquisition of NKG2C, KIRs, and CD57 is stimulated by a number of virus infections, including infection with human cytomegalovirus (CMV), hantavirus, chikungunya virus, and HIV-1. Here, we addressed if HSV-2 infection in a similar way drives NK cell differentiation towards an NKG2A(-)NKG2C(+)KIR(+)CD57(+) phenotype. In contrast to infection with CMV, hantavirus, chikungunya virus, and HIV-1, recurrent HSV-2 infection did not yield an accumulation of highly differentiated NK cells in human peripheral blood. This outcome indicates that human HSV-2 infection has no significant imprinting effect on the human NK cell repertoire.
    PLoS ONE 11/2011; 6(11):e27664. DOI:10.1371/journal.pone.0027664 · 3.53 Impact Factor
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    ABSTRACT: CD94/NKG2A is an inhibitory receptor that controls the activity of a large proportion of human NK cells following interactions with the nonclassical HLA class Ib molecule HLA-E expressed on target cells. In this study, we show that selenite (SeO(3)(2-)), an inorganic selenium compound, induces an almost complete loss of cell surface expression of HLA-E on tumor cells of various origins. Selenite abrogated the HLA-E expression at a posttranscriptional level, since selenite exposure led to a dose-dependent decrease in cellular HLA-E protein expression whereas the mRNA levels remained intact. The loss of HLA-E expression following selenite treatment was associated with decreased levels of intracellular free thiols in the tumor cells, suggesting that the reduced HLA-E protein synthesis was caused by oxidative stress. Indeed, HLA-E expression and the level of free thiols remained intact following treatment with selenomethionine, a selenium compound that does not generate oxidative stress. Loss of HLA-E expression, but not of total HLA class I expression, on tumor cells resulted in increased susceptibility to CD94/NK group 2A-positive NK cells. Our results suggest that selenite may be used to potentiate the anti-tumor cytotoxicity in settings of NK cell-based immunotherapies.
    The Journal of Immunology 09/2011; 187(7):3546-54. DOI:10.4049/jimmunol.1100610 · 5.36 Impact Factor
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    ABSTRACT: Invariant NKT cells are important in the activation and regulation of immune responses. They can also function as CD1d-restricted killer cells. However, the role of activating innate NK-cell receptors expressed on NKT cells in triggering cytolytic function is poorly characterized. Here, we initially confirmed that the cellular stress-ligand receptor NKG2D is expressed on CD4- NKT cells, whereas most CD4+ NKT cells lack this receptor. Interestingly, NKG2D+ NKT cells frequently expressed perforin, and both NKG2D and perforin localized at the site of contact with NKG2D ligand-expressing target cells. CD4- NKT cells degranulated in response to NKG2D engagement in a redirected activation assay independent of stimulation via their invariant TCR. NKT cells killed P815 cells coated with anti-NKG2D mAb and CD1d-negative K562 tumor target cells in an NKG2D-dependent manner. Furthermore, NKG2D engagement co-stimulated TCR-mediated NKT-cell activation in response to endogenous CD1d-presented ligands or suboptimal levels of anti-CD3 triggering. These data indicate that the CD4- subset of human NKT cells can mediate direct lysis of target cells via NKG2D engagement independent of CD1d, and that NKG2D also functions as a co-stimulatory receptor in these cells. NKG2D thus plays both a direct and a co-stimulatory role in the activation of NKT cells.
    European Journal of Immunology 07/2011; 41(7):1913-23. DOI:10.1002/eji.200940278 · 4.52 Impact Factor
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    ABSTRACT: We analyzed the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) over the past 2 decades. Between 1992 and 2009, 953 patients were treated with HSCT, mainly for a hematologic malignancy. They were divided according to 4 different time periods of treatment: 1992 to 1995, 1996 to 2000, 2001 to 2005, and 2006 to 2009. Over the years, many factors have changed considerably regarding patient age, diagnosis, disease stage, type of donor, stem cell source, genomic HLA typing, cell dose, type of conditioning, treatment of infections, use of granulocyte-colony stimulating factor (G-CSF), use of mesenchymal stem cells, use of cytotoxic T cells, and home care. When we compared the last period (2006-2009) with earlier periods, we found slower neutrophil engraftment, a higher incidence of acute graft-versus-host disease (aGVHD) of grades II-IV, and less chronic GVHD (cGHVD). The incidence of relapse was unchanged over the 4 periods (22%-25%). Overall survival (OS) and transplant-related mortality (TRM) improved significantly in the more recent periods, with the best results during the last period (2006-2009) and a 100-day TRM of 5.5%. This improvement was also apparent in a multivariate analysis. When correcting for differences between the 4 groups, the hazard ratio for mortality in the last period was 0.59 (95% confidence interval [CI]: 0.44-0.79; P < .001) and for TRM it was 0.63 (CI: 0.43-0.92; P = .02). This study shows that the combined efforts to improve outcome after HSCT have been very effective. Even though we now treat older patients with more advanced disease and use more alternative HLA nonidentical donors, OS and TRM have improved. The problem of relapse still has to be remedied. Thus, several different developments together have resulted in significantly lower TRM and improved survival after HSCT over the last few years.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2011; 17(11):1688-97. DOI:10.1016/j.bbmt.2011.05.001 · 3.35 Impact Factor
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    ABSTRACT: Natural killer (NK) cells are known to mount a rapid response to several virus infections. In experimental models of acute viral infection, this response has been characterized by prompt NK cell activation and expansion followed by rapid contraction. In contrast to experimental model systems, much less is known about NK cell responses to acute viral infections in humans. We demonstrate that NK cells can rapidly expand and persist at highly elevated levels for >60 d after human hantavirus infection. A large part of the expanding NK cells expressed the activating receptor NKG2C and were functional in terms of expressing a licensing inhibitory killer cell immunoglobulin-like receptor (KIR) and ability to respond to target cell stimulation. These results demonstrate that NK cells can expand and remain elevated in numbers for a prolonged period of time in humans after a virus infection. In time, this response extends far beyond what is considered normal for an innate immune response.
    Journal of Experimental Medicine 01/2011; 208(1):13-21. DOI:10.1084/jem.20100762 · 13.91 Impact Factor
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    ABSTRACT: Variable interaction between the Bw4 epitope of HLA-B and the polymorphic KIR3DL1/S1 system of inhibitory and activating NK cell receptors diversifies the development, repertoire formation, and response of human NK cells. KIR3DL1*004, a common KIR3DL1 allotype, in combination with Bw4(+) HLA-B, slows progression of HIV infection to AIDS. Analysis in this study of KIR3DL1*004 membrane traffic in NK cells shows this allotype is largely misfolded but stably retained in the endoplasmic reticulum, where it binds to the chaperone calreticulin and does not induce the unfolded protein response. A small fraction of KIR3DL1*004 folds correctly and leaves the endoplasmic reticulum to be expressed on the surface of primary NK and transfected NKL cells, in a form that can be triggered to inhibit NK cell activation and secretion of IFN-γ. Consistent with this small proportion of correctly folded molecules, trace amounts of MHC class I coimmunoprecipitated with KIR3DL1*004. There was no indication of any extensive intracellular interaction between unfolded KIR3DL1*004 and cognate Bw4(+) HLA-B. A similarly limited interaction of Bw4 with KIR3DL1*002, when both were expressed by the same cell, was observed despite the efficient folding of KIR3DL1*002 and its abundance on the NK cell surface. Several positions of polymorphism modulate KIR3DL1 abundance at the cell surface, differences that do not necessarily correlate with the potency of allotype function. In this context, our results suggest the possibility that the effect of Bw4(+) HLA-B and KIR3DL1*004 in slowing progression to AIDS is mediated by interaction of Bw4(+) HLA-B with the small fraction of cell surface KIR3DL1*004.
    The Journal of Immunology 01/2011; 186(1):62-72. DOI:10.4049/jimmunol.0903657 · 5.36 Impact Factor

Publication Stats

2k Citations
415.45 Total Impact Points


  • 2012–2015
    • University of Oslo
      • • Institute of Clinical Medicine
      • • Institute for Cancer Research (ICR)
      Kristiania (historical), Oslo, Norway
  • 2012–2014
    • Oslo University Hospital
      • Institute for Cancer Research
      Kristiania (historical), Oslo County, Norway
  • 1999–2013
    • Karolinska Institutet
      • • Center for Infectious Medicine
      • • Institutionen för onkologi-patologi
      Solna, Stockholm, Sweden
  • 2005–2012
    • Karolinska University Hospital
      • Center for Infectious Medicine (CIM)
      Tukholma, Stockholm, Sweden
  • 2011
    • University of California, San Francisco
      • Department of Microbiology and Immunology
      San Francisco, CA, United States
  • 2007
    • Leiden University
      Leyden, South Holland, Netherlands