Lise Kveberg

• Orellana, Daniel Alfredo Palacios; Majhi, Rakesh Kumar; Szabo, Edina Krisztina; Clement, Dennis; Lachota, Mieszko Krzysztof & Netskar, Herman Krogstad [Show all 11 contributors for this article] (2024). The G Protein-Coupled Receptor GPR56 Is an Inhibitory Checkpoint for NK Cell Migration. Journal of Immunology. ISSN 0022-1767. 213(9), p. 1349–1357. doi: 10.4049/jimmunol.2400228. Full text in Research Archive
• Philippon, Camille; Tao, Sudan; Clement, Dennis; Haroun-Izquierdo, Alvaro; Kichula, Katherine M. & Netskar, Herman Krogstad [Show all 21 contributors for this article] (2023). Allelic variation of KIR and HLA tunes the cytolytic payload and determines functional hierarchy of NK cell repertoires. Blood Advances. ISSN 2473-9529. 7(16), p. 4492–4504. doi: 10.1182/bloodadvances.2023009827. Full text in Research Archive Show summary

  Abstract The functionality of natural killer (NK) cells is tuned during education and is associated with remodeling of the lysosomal compartment. We hypothesized that genetic variation in killer cell immunoglobulin-like receptor (KIR) and HLA, which is known to influence the functional strength of NK cells, fine-tunes the payload of effector molecules stored in secretory lysosomes. To address this possibility, we performed a high-resolution analysis of KIR and HLA class I genes in 365 blood donors and linked genotypes to granzyme B loading and functional phenotypes. We found that granzyme B levels varied across individuals but were stable over time in each individual and genetically determined by allelic variation in HLA class I genes. A broad mapping of surface receptors and lysosomal effector molecules revealed that DNAM-1 and granzyme B levels served as robust metric of the functional state in NK cells. Variation in granzyme B levels at rest was tightly linked to the lytic hit and downstream killing of major histocompatibility complex–deficient target cells. Together, these data provide insights into how variation in genetically hardwired receptor pairs tunes the releasable granzyme B pool in NK cells, resulting in predictable hierarchies in global NK cell function.

• Lachota, Mieszko; Zielniok, Katarzyna; Orellana, Daniel Alfredo Palacios; Kanaya, Minoru; Peena, Leena & Hoel, Hanna Julie [Show all 11 contributors for this article] (2023). Mapping the chemotactic landscape in NK cells reveals subset-specific synergistic migratory responses to dual chemokine receptor ligation. EBioMedicine. 96. doi: 10.1016/j.ebiom.2023.104811. Full text in Research Archive Show summary

  Background Natural killer (NK) cells have a unique capability of spontaneous cytotoxicity against malignant cells and hold promise for off-the-shelf cell therapy against cancer. One of the key challenges in the field is to improve NK cell homing to solid tumors. Methods To gain a deeper understanding of the cellular mechanisms regulating trafficking of NK cells into the tumor, we used high-dimensional flow cytometry, mass cytometry, and single-cell RNA-sequencing combined with functional assays, creating a comprehensive map of human NK cell migration phenotypes. Findings We found that the chemokine receptor repertoire of peripheral blood NK cells changes in a coordinated manner becoming progressively more diversified during NK cell differentiation and correlating tightly with the migratory response of the distinct NK cell subsets. Simultaneous ligation of CXCR1/2 and CX3CR1, synergistically potentiated the migratory response of NK cells. Analysis of 9471 solid cancers from publicly available TCGA/TARGET repositories revealed dominant chemokine patterns that varied across tumor types but with no tumor group expressing ligands for more than one chemokine receptor present on mature NK cells. Interpretation The finding that chemokine stimulation can elicit a synergistic migratory response in NK cells combined with the identified lack of naturally occurring pairs of chemokines-chemokine receptors in human cancers may explain the systematic exclusion of NK cells from the tumor microenvironment and provides a basis for engineering next-generation NK cell therapies against malignancies. Funding The Polish Ministry of Science and Higher Education, the National Science Centre, Poland, The Norwegian Cancer Society, the Norwegian Research Council, the South-Eastern Norway Regional Health Authority, The Swedish Cancer Society, the Swedish Children's Cancer Foundation, The Swedish Research Council, The Center of Excellence: Precision Immunotherapy Alliance, Knut and Alice Wallenberg Foundation and National Cancer Institute.

• Haroun-Izquierdo, Alvaro; Vincenti, Marianna; Netskar, Herman Krogstad; Ooijen, Hanna van; Zhang, Bin & Bendzick, Laura [Show all 30 contributors for this article] (2022). Adaptive single-KIR+NKG2C+ NK cells expanded from select superdonors show potent missing-self reactivity and efficiently control HLA-mismatched acute myeloid leukemia. Journal for ImmunoTherapy of Cancer (JITC). 10:e005577(11), p. 1–13. doi: 10.1136/jitc-2022-005577. Full text in Research Archive Show summary

  Background Natural killer (NK) cells hold great promise as a source for allogeneic cell therapy against hematological malignancies, including acute myeloid leukemia (AML). Current treatments are hampered by variability in NK cell subset responses, a limitation which could be circumvented by specific expansion of highly potent single killer immunoglobulin-like receptor (KIR)+NKG2C+ adaptive NK cells to maximize missing-self reactivity. Methods We developed a GMP-compliant protocol to expand adaptive NK cells from cryopreserved cells derived from select third-party superdonors, that is, donors harboring large adaptive NK cell subsets with desired KIR specificities at baseline. We studied the adaptive state of the cell product (ADAPT-NK) by flow cytometry and mass cytometry as well as cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq). We investigated the functional responses of ADAPT-NK cells against a wide range of tumor target cell lines and primary AML samples using flow cytometry and IncuCyte as well as in a mouse model of AML. Results ADAPT-NK cells were >90% pure with a homogeneous expression of a single self-HLA specific KIR and expanded a median of 470-fold. The ADAPT-NK cells largely retained their adaptive transcriptional signature with activation of effector programs without signs of exhaustion. ADAPT-NK cells showed high degranulation capacity and efficient killing of HLA-C/KIR mismatched tumor cell lines as well as primary leukemic blasts from AML patients. Finally, the expanded adaptive NK cells had preserved robust antibody-dependent cellular cytotoxicity potential and combination of ADAPT-NK cells with an anti-CD16/IL-15/anti-CD33 tri-specific engager led to near-complete killing of resistant CD45dim blast subtypes. Conclusions These preclinical data demonstrate the feasibility of off-the-shelf therapy with a non-engineered, yet highly specific, NK cell population with full missing-self recognition capability.

• Pfefferle, Aline; Jacobs, Benedikt Marcel; Haroun-Izquierdo, Alvaro; Kveberg, Lise; Sohlberg, Ebba & Malmberg, Karl-Johan (2020). Deciphering natural killer cell homeostasis. Frontiers in Immunology. 11:812, p. 1–11. doi: 10.3389/fimmu.2020.00812. Full text in Research Archive Show summary

  Natural killer (NK) cells have a central role within the innate immune system, eliminating virally infected, foreign and transformed cells through their natural cytotoxic capacity. Release of their cytotoxic granules is tightly controlled through the balance of a large repertoire of inhibitory and activating receptors, and it is the unique combination of these receptors expressed by individual cells that confers immense diversity both in phenotype and functionality. The diverse, yet unique, NK cell repertoire within an individual is surprisingly stable over time considering the constant renewal of these cells at steady state. Here we give an overview of NK cell differentiation and discuss metabolic requirements, intra-lineage plasticity and transcriptional reprogramming during IL-15-driven homeostatic proliferation. New insights into the regulation of NK cell differentiation and homeostasis could pave the way for the successful implementation of NK cell-based immunotherapy against cancer.

• Boieri, Margherita; ULVMOEN, AINA; Sudworth, Amanda; Lendrem, Clare; Collin, Matthew & Dickinson, Anne M. [Show all 8 contributors for this article] (2017). IL-12, IL-15, and IL-18 pre-activated NK cells target resistant T cell acute lymphoblastic leukemia and delay leukemia development in vivo. Oncoimmunology. ISSN 2162-4011. 6(3:e1274478), p. 1–13. doi: 10.1080/2162402X.2016.1274478. Full text in Research Archive Show summary

  NK cells have shown promise in therapy of hematological cancers, in particular against acute myeloid leukemia. In contrast, the more NK cell-resistant acute lymphoblastic leukemia (ALL) is difficult to treat with NK-cell-based therapies, and we hypothesized that pre-activation of NK cells could overcome this resistance. We show in pediatric and adult patients with T-cell ALL (T-ALL) perturbed NK cell effector functions at diagnosis. Using an in vivo rat model for T-ALL, Roser leukemia (RL), suppressed NK cell effector functions were observed. NK cells from T-ALL patients had reduced expression of the activating receptors NKp46 and DNAM-1, but not NKG2D. In contrast to T-ALL patients, NKG2D but not NKp46 was downregulated on NK cells during rat RL. Decreased frequencies of terminally differentiated NKG2A+CD57−CD56dim NK cells in human T-ALL was paralleled in the rat by reduced frequencies of bone marrow NK cells expressing the maturation marker CD11b, possibly indicating impairment of differentiation during leukemia. RL was highly resistant to autologous NK cells, but this resistance was overcome upon pre-activation of NK cells with IL-12, IL-15, and IL-18, with concomitant upregulation of activation markers and activating receptors. Importantly, adoptive transfers of IL-12, IL-15, and IL-18 pre-activated NK cells significantly slowed progression of RL in vivo. The data thus shows that T-ALL blasts normally resistant to NK cells may be targeted by cytokine pre-activated autologous NK cells, and this approach could have potential implications for immunotherapeutic protocols using NK cells to more efficiently target leukemia.

• Sudworth, Amanda; Vaage, John T.; Inngjerdingen, Marit & Kveberg, Lise (2017). Frontline Science: A hyporesponsive subset of rat NK cells negative for Ly49s3 and NKR-P1B are precursors to the functionally mature NKR-P1B+ subset. Journal of Leukocyte Biology. ISSN 0741-5400. 102(6), p. 1289–1298. doi: 10.1189/jlb.1HI0517-177RR. Full text in Research Archive Show summary

  Rat NK cells are divided into major subsets expressing either Ly49 receptors or the inhibitory NKR‐P1B receptor in conjunction with NKG2A/C/E receptors. A minor subset of NKp46+ cells lacking expression of both Ly49 receptors and NKR‐P1B is present in blood and spleen and is associated with decreased functional competence. We hypothesized that this subset may represent precursors to Ly49+ and/or NKR‐P1B+ NK cells. When cultured in vitro in IL‐2 and IL‐15 or adoptively transferred to syngeneic hosts, a portion of NKR‐P1B−Ly49s3− cells transformed to express NKR‐P1B, but very little Ly49s3. Acquisition of NKR‐P1B by NKR‐P1B−Ly49s3− cells coincided with increased degranulation. In addition, although NKR‐P1B−Ly49s3− cells highly proliferate, proliferative activity was reduced upon acquisition of NKR‐P1B at comparable levels to bona fide NKR‐P1B+ NK cells. A fraction of NKR‐P1B−Ly49s3− cells remained negative for NKR‐P1B, both in vitro and after adoptive transfer in vivo. Most NKR‐P1B−Ly49s3− cells expressed the transcription factor Eomesodermin and NK cell markers, indicating that these cells represent conventional NK cells. Our findings suggest that the NKR‐P1B−Ly49s3− NK cells are precursors to NKR‐P1B single‐positive cells and that functional competence is acquired upon expression of NKR‐P1B.

• Sudworth, Amanda; Dai, Kezheng; Vaage, John T. & Kveberg, Lise (2016). Degranulation Response in Cytotoxic Rat Lymphocytes Measured with a Novel CD107a Antibody. Frontiers in Immunology. 7(572). doi: 10.3389/fimmu.2016.00572. Full text in Research Archive Show summary

  Measuring degranulation through CD107a expression has become an advantageous tool for testing the functional capacity of cytotoxic cells. Such functional studies have been hampered in the rat by the lack of a suitable anti-rat CD107a antibody. In this study, we report a novel hybridoma generated by immunizing Armenian inbred hamsters with transfected Chinese hamster ovary cells expressing CD107a. The SIM1 clone exhibited specific reactivity with CD107a and measured degranulation from natural killer (NK) cells stimulated with target cells or mAb crosslinking of their activating receptors. Degranulation in IL-2-activated NK cells could also be measured, when using low effector to target ratios. SIM1 also stained activated CD8, but not CD4 T cells. This report characterizes the degranulation response in cytotoxic rat cells with a new antibody against rat CD107a.

• Leibelt, S; Friede, ME; Rohe, C; Gütle, D; Rutkowski, E & Weigert, A [Show all 10 contributors for this article] (2015). Dedicated immunosensing of the mouse intestinal epithelium facilitated by a pair of genetically coupled lectin-like receptors. Mucosal Immunology. ISSN 1933-0219. 8(2), p. 232–242. doi: 10.1038/mi.2014.60. Full text in Research Archive
• Todros-Dawda, Izabela Malgorzata; Kveberg, Lise; Vaage, John Torgils & Inngjerdingen, Marit (2014). The tetraspanin CD53 modulates responses from activating NK cell receptors, promoting LFA-1 activation and dampening NK cell effector functions. PLOS ONE. 9(5). doi: 10.1371/journal.pone.0097844. Full text in Research Archive
• Kveberg, Lise; Sudworth, Amanda; Todros-Dawda, Izabela Malgorzata; Inngjerdingen, Marit & Vaage, John Torgils (2014). Functional characterization of a conserved pair of NKR-P1 receptors expressed by NK cells and T lymphocytes in liver and gut. European Journal of Immunology. ISSN 0014-2980. 45(2), p. 501–512. doi: 10.1002/eji.201444710. Full text in Research Archive
• Daws, Michael Rory; Dai, Kezheng; Zinöcker, Severin; Naper, Christian; Kveberg, Lise & Hedrich, Hans J [Show all 8 contributors for this article] (2012). Identification of an MHC Class I Ligand for the Single Member of a Killer Cell Lectin-like Receptor Family, KLRH1. Journal of Immunology. ISSN 0022-1767. 189(11), p. 5178–5184. doi: 10.4049/jimmunol.1201983. Full text in Research Archive Show summary

  Natural killer cells are able to recognize and kill target cells according to differences in MHC class I expression. In rodents, the Ly49 receptors are primarily responsible for this MHC differentiation. We previously described the cloning of a novel C-type lectin–like receptor, KLRH1, encoded in the NK complex adjacent to the Ly49 genes and expressed by subsets of NK and NKT cells. MHC influence on selection of KLRH1+ NK cells in congenic strains suggested that KLRH1 may have an MHC ligand, although we were unable to identify any such ligand. In this study, we have used a sensitive reporter system and Fc fusion protein to demonstrate that KLRH1 binds specifically to the classical MHC class I molecule RT1-A2 of the RT1n haplotype. Cytolytic activity of KLRH1-transfected RNK-16 cells was also inhibited by target cells expressing RT1-A2n. Thus, KLRH1 represents a novel family of MHC allele–specific inhibitory receptors expressed by NK cells.

• Inngjerdingen, Marit; Kveberg, Lise & Vaage, John Torgils (2012). A Novel NKR-P1B(bright) NK Cell Subset Expresses an Activated CD25(+)CX(3)CR1(+)CD62L(-)CD11b(-)CD27(-) Phenotype and Is Prevalent in Blood, Liver, and Gut-Associated Lymphoid Organs of Rats. Journal of Immunology. ISSN 0022-1767. 188(6), p. 2499–2508. doi: 10.4049/jimmunol.1003939. Full text in Research Archive
• Kveberg, Lise; Dai, Kezheng; Inngjerdingen, Marit; Brooks, Colin G.; Fossum, Sigbjørn & Vaage, John Torgils (2011). Phylogenetic and functional conservation of the NKR-P1F and NKR-P1G receptors in rat and mouse. Immunogenetics. ISSN 0093-7711. 63(7), p. 429–436. doi: 10.1007/s00251-011-0520-1. Full text in Research Archive
• Inngjerdingen, Marit; Kveberg, Lise; Naper, Christian & Vaage, John Torgils (2011). Natural killer cell subsets in man and rodents. Tissue Antigens. ISSN 0001-2815. 78(2), p. 81–88. doi: 10.1111/j.1399-0039.2011.01714.x. Full text in Research Archive
• Naper, Christian; Kveberg, Lise; Engh, Espen; Nestvold, Janne M.; Rolstad, Bent & Vaage, John Torgils (2010). Partial NK cell tolerance induced by radioresistant host cells in rats transplanted with MHC-mismatched bone marrow. International Immunology. ISSN 0953-8178. 22(12), p. 973–980. doi: 10.1093/intimm/dxq452. Full text in Research Archive
• Kveberg, Lise; Jiminèz-Royo, Pilar; Naper, Christian; Rolstad, Bent; Butcher, Geoffrey W & Vaage, John Torgils [Show all 7 contributors for this article] (2010). Two complementary rat NK cell subsets, Ly49s3(+) and NKR-P1B(+), differ in phenotypic characteristics and responsiveness to cytokines. Journal of Leukocyte Biology. ISSN 0741-5400. 88(1), p. 87–93. doi: 10.1189/jlb.0110039. Full text in Research Archive
• Kveberg, Lise; Dai, Kezheng; Westgaard, Ingunn Hagen; Daws, Michael Rory; Fossum, Sigbjørn & Naper, Christian [Show all 7 contributors for this article] (2009). Two major groups of rat NKR-P1 receptors can be distinguished based on chromosomal localization, phylogenetic analysis and Clr ligand binding. European Journal of Immunology. ISSN 0014-2980. 39(2), p. 541–551. doi: 10.1002/eji.200838891. Full text in Research Archive
• Kveberg, Lise; Dai, Kezheng; Dissen, Erik; Ryan, James C.; Rolstad, Bent & Vaage, John Torgils [Show all 7 contributors for this article] (2006). Strain-dependent expression of four structurally related rat Ly49 receptors; correlation with NK gene complex haplotype and NK alloreactivity. Immunogenetics. ISSN 0093-7711. 58(11), p. 905–916. Full text in Research Archive
• Kveberg, Lise; Inngjerdingen, Marit & Rolstad, Bent (2006). The novel inhibitory NKR-P1C receptor and ly49s3 identify two complementary, functionally distinct NK cell subsets in rats. Journal of Immunology. ISSN 0022-1767. 176, p. 4133–4140. Full text in Research Archive
• Naper, Christian; Dai, Kezheng; Kveberg, Lise; Rolstad, Bent; Niemi, EC & Vaage, John Torgils [Show all 7 contributors for this article] (2005). Two structurally related rat Ly49 receptors with opposing functions (Ly49 stimulatory receptor 5 and Ly49 inhibitory receptor 5) recognize nonclassical MHC class Ib-encoded target ligands. Journal of Immunology. ISSN 0022-1767. 174. Full text in Research Archive
• Kveberg, Lise; Ryan, JC; Rolstad, Bent & Inngjerdingen, Marit (2005). Expression of regulator of G protein signalling proteins in natural killer cells, and their modulation by Ly49A and Ly49D. Immunology. ISSN 0019-2805. 115. Full text in Research Archive
• Naper, Christian; Hayashi, Shigenari; Kveberg, Lise; Niemi, Eréne C.; Lanier, Lewis L. & Vaage, John Torgils [Show all 7 contributors for this article] (2002). Ly-49s3 is a promiscuous activating rat NK cell receptor for nonclassical MHC class I-encoded target ligands. Journal of Immunology. ISSN 0022-1767. 169, p. 22–30. Full text in Research Archive
• Kveberg, Lise; Bryceson, Yenan; Inngjerdingen, Marit; Rolstad, Bent & Maghazachi, Azzam A. (2002). Sphingosine 1 phosphate induces the chemotaxis of human natural killer cells. Role for heterotrimeric G proteins and phosphoinositide 3 kinases. European Journal of Immunology. ISSN 0014-2980. 32, p. 1856–1864. Full text in Research Archive
• Naper, Christian; Hayashi, Shigenari; Løvik, Guro; Kveberg, Lise; Niemi, Eréne C. & Rolstad, Bent [Show all 9 contributors for this article] (2002). Characterization of a novel killer cell lectin-like receptor (KLRH1) expressed by alloreactive rat NK cells. Journal of Immunology. ISSN 0022-1767. p. 5147–5154. Full text in Research Archive

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• Kveberg, Lise (2024). Antibody technology from Jan Terje Andersen’s team in-licensed by Mage Biologics. [Internet]. PRIMA webpage. doi: https:/www.prima.uio.no/english/news-and-events/news/2023/antibodytech-inlicensing-magebio.html#%3A%7E%3Atext=This%20is%20a%20result%20of%20a%20long-term%20collaboration%2Cthe%20story%20on%20Inven2%E2%80%99s%20webpage%20and%20at%20MEDWATCH.. Full text in Research Archive
• Kveberg, Lise; Dai, Kezheng; Martinsen, Stine; Fossum, Sigbjørn & Vaage, John Torgils (2009). Phylogenetic and functional conservation of the NKR-P1G NK receptor in rat and mouse. Full text in Research Archive
• Kveberg, Lise; Fossum, Sigbjørn & Vaage, John Torgils (2009). Phylogenetic and functional conservation of the NKR-P1G receptor in rat and mouse. Full text in Research Archive
• Kveberg, Lise; Westgaard, Ingunn Hagen; Dai, Kezheng; Daws, Michael Rory; Fossum, Sigbjørn & Naper, Christian [Show all 7 contributors for this article] (2007). The NKR-P1 family of receptors in rat recognizes C-type lectin related molecules. Full text in Research Archive
• Kveberg, Lise; Westgaard, Ingunn Hagen; Dai, Kezheng; Daws, Michael Rory; Fossum, Sigbjørn & Naper, Christian [Show all 7 contributors for this article] (2007). The NKR-P1 family of receptors in rat recognizes C-type lectin-related molecules. Full text in Research Archive
• Inngjerdingen, Marit; Kveberg, Lise; Naper, Christian; Dai, Kezheng; Rolstad, Bent & Vaage, John Torgils (2007). Functional characterization of two major NK cell subsets in the rat, a Ly49+ and a NKR-P1C+ subset. Full text in Research Archive
• Kveberg, Lise; Back, Camilla; Dai, KZD; Inngjerdingen, Marit; Rolstad, Bent & Ryan, JCR [Show all 7 contributors for this article] (2006). The novel inhibitory NKR-P1C receptor and Ly49s3 identify two complementary, functionally distinct NK cell subsets in rats. Tissue Antigens. ISSN 0001-2815. 67, p. 562–562. Full text in Research Archive

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