Nicole Marquardt team – Human tissue-resident NK cells in homeostasis and disease

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

The team is part of the Jakob Michaëlsson research group at the Center for Infectious Medicine (CIM).

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.

NK cell research

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 the tissue-resident NK cells 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.

Methods used in our research

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
H7 Department of Medicine, Huddinge

Nicole completed her PhD in Hannover, Germany, in 2011, and got recruited to the Center for Infectious Medicine (CIM) the same year. Since 2018 she is an assistant professor at CIM.

Nicole has a long-standing expertise in the field of NK cell research, both in blood and tissues. Her research focuses 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
H7 Department of Medicine, Huddinge

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.

Demi joined the Nicole Marquardt team in November 2019 where she is focusing on the role of tissue-resident NK cells in cancer and respiratory viral infections such as influenza virus and SARS-CoV-2. 

Nicole Wild

MSc, PhD student
H7 Department of Medicine, Huddinge

Nicole (aka Nici) earned her Bachelor’s degree at the Medical University of Innsbruck in 2018, and her Master’s degree at Karolinska Institutet in 2020. She worked as a Research Assistant with a focus on highly pathogenic viruses at the Robert Koch-Institute in Berlin, Germany. In April 2022, Nici got recruited as a PhD student to the Nicole Marquardt team, where she will mainly decipher the regulation of NK cells in different areas of the human lung in health and disease (respiratory viral infections, lung cancer).

Pablo Clavero

Internship student

Having finished his Bachelor’s degree in Biomedical Sciences at Universidad Autónoma de Barcelona (Spain), Pablo joined the Nicole Marquardt team in February 2022.

He is focusing on a project identifying phenotypic and functional characteristics of NK cells and T cells in Pemphigus vulgaris patients. Furthermore, Pablo is analyzing high-parameter flow cytometry data from an ongoing study, in order to determine differences of T cell subsets in different areas of the human lung as well as other matched organs.

 

Previous team members

  • Giampiero Valenzano, Internship student (January - July 2021)
  • Kathleen Schlüter, Internship student (April - June 2021)
  • Andreas von Kries, Internship/Master student (January 2020 - February 2021)
    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

  • Vetenskapsrådet (two distinct projects)
  • KI funding for doctoral education (KID, 100% funding of doctoral position)
  • CIMED (Awarded “Rising Star 2020”)
  • Karolinska Institutet
  • Groschinsky
  • Stiftelsen Tornspiran
  • Åke Wibergs Stiftelse
  • Magnus Bergvalls Stiftelse

Selected publications

  1. Comparison of Lung-Homing Receptor Expression and Activation Profiles on NK Cell and T Cell Subsets in COVID-19 and Influenza.
    Brownlie D, Rødahl I, Varnaite R, Asgeirsson H, Glans H, Falck-Jones S, Vangeti S, Buggert M, Ljunggren HG, Michaëlsson J, Gredmark-Russ S, Smed-Sörensen A, Marquardt N. Front Immunol 2022 ;13():834862. PMID: 35371005
     
  2. Expansions of adaptive-like NK cells with a tissue-resident phenotype in human lung and blood.
    Brownlie D, Scharenberg M, Mold JE, Hård J, Kekäläinen E, Buggert M, Nguyen S, Wilson JN, Al-Ameri M, Ljunggren HG, Marquardt N, Michaëlsson J. Proc Natl Acad Sci U S A 2021 03;118(11): PMID: 33836578* Shared senior authorship.
     
  3. Distinct developmental pathways from blood monocytes generate human lung macrophage diversity.
    Evren E, Ringqvist E, Tripathi KP, Sleiers N, Rives IC, Alisjahbana A, Gao Y, Sarhan D, Halle T, Sorini C, Lepzien R, Marquardt N, Michaëlsson J, Smed-Sörensen A, Botling J, Karlsson MCI, Villablanca EJ, Willinger T. Immunity 2021 02;54(2):259-275.e7. PMID:33382972
     
  4. Natural killer cell immunotypes related to COVID-19 disease severity.
    Maucourant C, Filipovic I, Ponzetta A, Aleman S, Cornillet M, Hertwig L, Strunz B, Lentini A, Reinius B, Brownlie D, Cuapio A, Ask EH, Hull RM, Haroun-Izquierdo A, Schaffer M, Klingström J, Folkesson E, Buggert M, Sandberg JK, Eriksson LI, Rooyackers O, Ljunggren HG, Malmberg KJ, Michaëlsson J, Marquardt N, Hammer Q, Strålin K, Björkström NK, Sci Immunol 2020 08;5(50): PMID: 32826343
     
  5. NK cells are activated and primed for skin-homing during acute dengue virus infection in humans.
    Zimmer CL, Cornillet M, Solà-Riera C, Cheung KW, Ivarsson MA, Lim MQ, Marquardt N, Leo YS, Lye DC, Klingström J, MacAry PA, Ljunggren HG, Rivino L, Björkström NK
    Nat Commun 2019 08;10(1):3897 PMID:31467285
     
  6. Unique transcriptional and protein-expression signature in human lung tissue-resident NK cells.
    Marquardt N, Kekäläinen E, Chen P, Lourda M, Wilson JN, Scharenberg M, Bergman P, Al-Ameri M, Hård J, Mold JE, Ljunggren HG, Michaëlsson J. Nat Commun 2019 08;10(1):3841 PMID31451696
     
  7. Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells.
    Scharenberg M, Vangeti S, Kekäläinen E, Bergman P, Al-Ameri M, Johansson N, Sondén K, Falck-Jones S, Färnert A, Ljunggren HG, Michaëlsson J, Smed-Sörensen A, Marquardt N. Front Immunol 2019 ;10():1116 PMID:31156653
     
  8. CD49a Expression Defines Tissue-Resident CD8+ T Cells Poised for Cytotoxic Function in Human Skin.
    Cheuk S, Schlums H, Gallais Sérézal I, Martini E, Chiang SC, Marquardt N, Gibbs A, Detlofsson E, Introini A, Forkel M, Höög C, Tjernlund A, Michaëlsson J, Folkersen L, Mjösberg J, Blomqvist L, Ehrström M, Ståhle M, Bryceson YT, Eidsmo L
    Immunity 2017 02;46(2):287-300 PMID28214226
     
  9. Human lung natural killer cells are predominantly comprised of highly differentiated hypofunctional CD69-CD56dim cells.
    Marquardt N, Kekäläinen E, Chen P, Kvedaraite E, Wilson JN, Ivarsson MA, Mjösberg J, Berglin L, Säfholm J, Manson ML, Adner M, Al-Ameri M, Bergman P, Orre AC, Svensson M, Dahlén B, Dahlén SE, Ljunggren HG, Michaëlsson J. J Allergy Clin Immunol 2017 Apr;139(4):1321-1330.e4 PMID: 27670241
     
  10. Fetal CD103+ IL-17-Producing Group 3 Innate Lymphoid Cells Represent the Dominant Lymphocyte Subset in Human Amniotic Fluid.
    Marquardt N, Ivarsson MA, Sundström E, Åkesson E, Martini E, Eidsmo L, Mjösberg J, Friberg D, Kublickas M, Ek S, Tegerstedt G, Seiger Å, Westgren M, Michaëlsson J
    J Immunol 2016 10;197(8):3069-3075 PMID27591320