Team Nicole Marquardt

Our research focuses on the biology of human NK cells in tissues and their role in tissue-specific pathologies.

Human NK cells are well-characterized in the peripheral blood, however, rather little is known about NK cells in tissues. While peripheral blood NK cells likely play an important role in hematologic malignancies, tissue-resident NK cells presumably represent a front line of defense in tissues such as the lung e.g. during respiratory viral infections or play a pivotal role in the defense against solid tumors. Hence, the identification of distinct NK cell subsets homing to and residing in human tissues allows us to gain new perspectives about disease development, progression, and potential therapeutic approaches in tissue-specific pathologies.

The team's focus

In our team, we focus particularly on NK cells in human lung (healthy, tumor-free, tumor, respiratory viral infections), in human sarcoma tumors, as well as tissue-homing capacities of blood NK cells. The combination of access to unique human tissue biopsies and matched peripheral blood, high-parameter flow cytometry (up to 29 colours), cell sorting, and RNA-sequencing enables us to map the distinct characteristics of human tissue-resident NK cells in health and disease.

Team leader

Nicole Marquardt

Dr. rer. nat., Assistant Professor

Nicole completed her PhD in Hannover, Germany, in 2011, got recruited to the Center for Infectious Medicine, CIM in the same year. Since 2018 she is an assistant professor at CIM. She has a long-standing expertise in the field of NK cell research, both in blood and tissues. Nicole is leading a team within the Michaëlsson group, focusing primarily on human NK cells in lung tissue under homeostasis and disease (respiratory viral infections and cancer) as well as in sarcoma tumors.

Team members

Demi Brownlie

PhD, Postdoc

Demi completed her doctoral studies in 2019 at the University of Edinburgh in Scotland where she investigated the suppression of NK cells by tumor-associated macrophages in mouse models of pulmonary metastatic breast cancer. She joined the Team Marquardt in November 2019 and is focusing on the role of tissue-resident NK cells in cancer (sarcoma, lung) and respiratory viral infections such as influenza virus and SARS-CoV-2.  

Giampiero Valenzano

Internship student

Giampiero joined the Team Marquardt in January 2021 for an elective internship as a visiting student from the International Medical School at Sapienza University of Rome, Italy. Giampiero gained previous research experience from working at HERM (KI, Bryceson group) with a focus on CD8+ tissue-resident memory T cells (TRM). In our team he will be studying phenotypic and functional characteristics of NK cells from distinct human tissues and tissue/tumor-infiltration mechanisms of human blood NK cells.      

Kathleen Schlüter

Internship student

Kathleen joined the Team Marquardt in April 2021 for an elective internship from the University of Lübeck, Germany. Kathleen has a strong interest in immunology and virology, holding a Bachelor degree in virology. At CIM, Kathleen will be working on a collaborative project with the Philipps-University of Marburg, Germany. For this, she will use 28-colour flow cytometry and investigate the role of human NK cells and T cells in Pemphigus vulgaris, a rare autoimmune disorder. Finally, Kathleen will also be involved in our studies on NK cells in lung tissue.

 

Previous team members

Andreas von Kries, Internship/Master student. Now PhD-student in the group of Adelheid Cerwenka, Mannheim, Germany

Projects

Prevention of NK cell-induced lung tissue-damage upon severe respiratory viral infections

Severe respiratory diseases such as COVID-19 and flu are commonly associated with lung tissue-damage, partly caused by an excessive immune response. While Natural Killer (NK) cells are believed to play a crucial role in host responses towards viral infections, surprisingly little is known about human NK cell regulation in respiratory viral infections.

The overall aim with this project is to identify regulatory mechanisms of human blood and lung NK cells that can be targeted for treatment of patients suffering from severe acute respiratory viral infections, ultimately balancing immune pathology and immune protection in severe respiratory viral infections.

Ongoing collaborations will provide us access to non-infected human lung tissue, lung tissue from COVID-19-infected patients as well as to peripheral blood from influenza- or SARS-CoV-2-infected patients. The combination of unique human clinical material, the ability to conduct in vitro infections with highly relevant viruses, and usage of cutting-edge technologies will be the central elements of this project. My vision is to define the biology of human NK cell subsets in and trafficking to the lung upon viral infection, ultimately aiming at reducing disease severity, hospitalization, and mortality.

Tissue-resident NK cells in the human lung and lung tumors

Lung cancer is the leading type of cancer worldwide in terms of incidence and mortality. Natural Killer (NK) cells are well known for their capacity to target and lyse tumor cells, and they are currently representing a promising tool for treatment of hematopoietic cancers. However, treatment of solid tumors including lung tumors is still in its infancy. Major limitations are inefficient trafficking of NK cells to the tumor site as well as lack of NK cell infiltration into the tumor, antigen escape mechanisms, and an immunosuppressive tumor microenvironment. While we have identified distinct NK cell subsets in the human lung in previous studies, very little is known about the regulation of NK cells in the human lung and in lung tumors. This project aims at mapping the landscape of NK cells in different areas of healthy human lung and in human lung tumors. Based on the results, we aim at harnessing and expanding the NK cell subsets most suitable for infiltrating and killing lung tumor cells for future treatment of lung cancer.

In collaboration with physicians and scientists at Karolinska University Hospitals Huddinge/Solna we will collect healthy lung tissue from human organ donors as well as tumor-free tissue and lung tumors from patients undergoing surgery for suspected lung cancer. We will particularly focus on NK cell lung-homing, tumor-infiltration, tissue-residency, and cytotoxicity. Cutting-edge technologies such as 29-colour flow cytometry, RNA-sequencing, and live cell-imaging are key in this project proposal.

The combination of unique human clinical material and application of cutting-edge technologies will be the central elements of this project. Our vision is to harness suitable human NK cell subsets in lung cancer, ultimately aiming at reducing disease severity, hospitalization, and mortality.

Research support

  • CIMED (Awarded “Rising Star 2020”)
  • Karolinska Institutet
  • Groschinsky
  • Stiftelsen Tornspiran
  • Åke Wibergs Stiftelse
  • Magnus Bergvalls Stiftelse

Publications

1. Brownlie, D.1, M. Scharenberg1, J. E. Mold, J. Hård, E. Kekäläinen, M. Buggert, Son Nguyen, J. N. Wilson, M. Al-Ameri, H.-G. Ljunggren, N. Marquardt2, and J. Michaëlsson2. 2020. High-dimensional analysis reveals a distinct population of adaptive-like tissue-resident NK cells in human lung. P.N.A.S. 118:e2016580118

1D.B. and M.S. contributed equally
2N.M. and J.M. contributed equally

2. Evren, E., E. Ringqvist, K. Parijat Tripathi, N. Sleiers, I. Có Rives, Y. Gao, D. Sarhan, C. Sorini, R. Lepzien, N. Marquardt, J. Michaëlsson, A. Smed-Sörensen, M.C.I. Karlsson, E.J. Villablanca, T. Willinger. 2020. Mapping the monocytic origin of lung macrophages indentifies new pathways of human macrophage ontogeny. Immunity 54, 1-17

3. Maucourant, C., I. Filipovic, A. Ponzetta, S. Aleman, M. Cornillet, L. Hertwig, B. Strunz, A. Lentini, B. Reinius, D. Brownlie, A. Cuapio, E. Heggernes Ask, R. M. Hull, A. Harous-Izquierdo, M. Schaffer, J. Klingström, E. Folkesson, M. Buggert, J. K. Sandberg, L. I. Eriksson, O. Rooyackers, H.-G. Ljunggren, K.-J. Malmberg, J. Michaëlsson, N. Marquardt, Q. Hammer, K. Strålin, N.K. Björkström. 2020. Natural Killer cell immunotypes related to COVID-19 disease severity. Sci Immunol. 5: 50, eabd6832

4. Zimmer, C. L., M. Cornillet, C. Solà-Riera, K.-W. Cheung, M. A. Ivarsson, M. Q. Lim, N. Marquardt, Y.-S. Leo, D. C. Lye, J. Klingström, P. A. MacAry, H.-G. Ljunggren, L. Rivino, and N. K. Björkström. 2019. NK cells are activated and primed for skin-homing during acute dengue virus infection in humans. Nat Commun 10: 3897.

5. Marquardt, N., E. Kekäläinen, P. Chen, M. Lourda, J. N. Wilson, M. Scharenberg, P. Bergman, M. Al-Ameri, J. Hård, J. E. Mold, H.-G. Ljunggren, and J. Michaëlsson. 2019. Unique transcriptional and protein-expression signature in human lung tissue-resident NK cells. Nat Commun 10: 3841–12.

6. Scharenberg, M., S. Vangeti, E. Kekäläinen, P. Bergman, M. Al-Ameri, N. Johansson, K. Sondén, S. Falck-Jones, A. Färnert, H.-G. Ljunggren, J. Michaëlsson, A. Smed-Sörensen, and N. Marquardt. 2019. Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells. Front Immunol 10: 1116.

7. Marquardt, N., E. Kekäläinen, P. Chen, E. Kvedaraite, J. N. Wilson, M. A. Ivarsson, J. Mjösberg, L. Berglin, J. Säfholm, M. L. Manson, M. Adner, M. Al-Ameri, P. Bergman, A.-C. Orre, M. Svensson, B. Dahlén, S.-E. Dahlén, H.-G. Ljunggren, and J. Michaëlsson. 2016. Human Lung NK Cells are Predominantly Comprised of Highly Differentiated Hypofunctional CD69(-)CD56(dim) Cells. J. Allergy Clin. Immunol. 139: 1321–1330.e4.

8. Cheuk, S., H. Schlums, I. Gallais Sérézal, E. Martini, S. C. Chiang, N. Marquardt, A. Gibbs, E. Detlofsson, A. Introini, M. Forkel, C. Höög, A. Tjernlund, J. Michaëlsson, L. Folkersen, J. Mjösberg, L. Blomqvist, M. Ehrström, M. Ståhle, Y. T. Bryceson, and L. Eidsmo. 2017. CD49a Expression Defines Tissue-Resident CD8(+) T Cells Poised for Cytotoxic Function in Human Skin. Immunity 46: 287–300.

9. Marquardt, N., M. A. Ivarsson, E. Sundström, E. Åkesson, E. Martini, L. Eidsmo, J. Mjösberg, D. Friberg, M. Kublickas, S. Ek, G. Tegerstedt, Å. Seiger, M. Westgren, and J. Michaëlsson. 2016. Fetal CD103+ IL-17-Producing Group 3 Innate Lymphoid Cells Represent the Dominant Lymphocyte Subset in Human Amniotic Fluid. J. Immunol.: 197(8):3069-3075

10. Marquardt, N., M. A. Ivarsson, K. Blom, V. D. Gonzalez, M. Braun, K. Falconer, R. Gustafsson, A. Fogdell-Hahn, J. K. Sandberg, and J. Michaëlsson. 2015. The Human NK Cell Response to Yellow Fever Virus 17D Is Primarily Governed by NK Cell Differentiation Independently of NK Cell Education. J. Immunol. 195: 3262–3272.

11. Marquardt, N., V. Béziat, S. Nyström, J. Hengst, M. A. Ivarsson, E. Kekäläinen, H. Johansson, J. Mjösberg, M. Westgren, T. O. Lankisch, H. Wedemeyer, E. C. Ellis, H.-G. Ljunggren, J. Michaëlsson, and N. K. Björkström. 2015. Cutting Edge: Identification and Characterization of Human Intrahepatic CD49a+ NK Cells. J. Immunol. 194: 2467–2471.

12. Ivarsson, M. A., L. Loh, N. Marquardt, E. Kekäläinen, L. Berglin, N. K. Björkström, M. Westgren, D. F. Nixon, and J. Michaëlsson. 2013. Differentiation and functional regulation of human fetal NK cells. The Journal of clinical investigation 123: 3889–3901.

Available as preprint

1. Brownlie, D., I. Rødahl, R. Varnaite, H. Asgeirsson, H. Glans, S. Falck-Jones, S. Vangeti, M. Buggert, H.G. Ljunggren, J. Michaëlsson, S. Gredmark-Russ, A. Smed-Sörensen, and N. Marquardt. Distinct lung-homing receptor expression and activation profiles on NK cell and T cell subsets in COVID-19 and influenza. BioRxiv. 2021