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Jakob Michaelsson group

The main focus of our research is to investigate the differentiation, function and regulation of human Natural Killer (NK) cells and CD8 T cells during fetal development and in adults.

Jakob Michaelsson
Jakob Michaelsson, Group leader

Understanding how these cells develop and function during different stages of life, and during different conditions is important to achieve the long-term goal of our research, which is to aid in the development of new therapies in infectious diseases, cancer and transplantation. We continuously develop new techniques for advanced analysis of immune cells, and strive to be leading in flow cytometry analysis of human NK cells and T cells (currently 29-colour flow cytometry).

Keywords: NK cells, ILCs, CD8 T cells, development, differentiation, virus infection

Members

Jakob Michaëlsson

Group leader, PhD, Associate Professor

He was recruited to the Center for Infectious Medicine as a principal investigator in 2005, after 2 years as a postdoc at the Gladstone Institute of Virology and Immunology, University of California San Francisco. He received his PhD at the Karolinska Institute in 2002, with professor Klas Kärre as a supervisor. Jakob has a longstanding interest in human fetal immune development and the biology of human NK cells and T cells in health and disease.

Nicole Marquardt

PhD, Assistant Professor

Nicole completed her PhD in Hannover, Germany, in 2011, got recruited to the Center for Infectious Medicine (CIM) in the same year, and 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. Link to Nicole´s Team at the bottom of this page. 

Projects

Development of human innate lymphoid cells in fetal tissues

Little is known about how and where human immune cells develop and mature, and what signals are regulating innate lymphoid cell (ILC) development, including NK cells. We have previously investigated the development and function of fetal NK cells and T cells in the developing fetus, demonstrating that they are phenotypically and functionally distinct from those in adults. Within this project we are currently aiming at elucidating the developmental trajectories of human fetal ILCs from precursor stages to mature cells, and to investigate how fetal ILCs compare to adult ILCs in various human tissues. We believe that this project will provide important knowledge regarding the development of the human immune system that could have implications in for example in in utero therapies and for our understanding of immune responses in new born babies.

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

Most of our knowledge regarding human NK cell biology is based on studies of these cells in peripheral blood. Recently it has becoming increasingly clear that NK cells in tissues differ from those in tissues, with distinct phenotypes, function and possibly developmental origins. In this project we focus on the biology of tissue-resident NK cells in the human lung and what role they might play lung tumors. See also here (hyperlink to Marquardt page) for more information regarding the project.

Formation of the human memory CD8+ T cell repertoire at the clonal level

CD8+ T cells play an important role in our defense against viral infections and tumors. It is well known that antigen-specific CD8+ T cells expand in viral infections and eventually form a broad repertoire of memory CD8+ T cells that can help in protecting against subsequent infections with the same virus. In this project we collaborate with Dr Jeff Mold and the Frisén lab to investigate how the repertoire of memory CD8+ T cells is shaped by distinct clonal identities over time in response to vaccination against Yellow Fever virus.

Selected publications

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. “Unique transcriptional and protein-expression signature in human lung tissue-resident NK cells” 2019.
Nat Commun. 10:3841.

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. “Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells” 2019.
Front Immunol. 10:1116

Hård J, Al Hakim E, Kindblom M, Björklund ÅK, Sennblad B, Demirci I, Paterlini M, Reu P, Borgström E, Ståhl PL, Michaelsson J, Mold JE, Frisén J. 2019. “Conbase: a software for unsupervised discovery of clonal somatic mutations in single cells through read phasing” 2019.
Genome Biol. 20:68

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. ”Human lung natural killer cells are predominantly comprised of highly differentiated hypofunctional CD69-CD56dim cells” 2017
J Allergy Clin Immunol. 139:1321-1330

Reinius B, Mold JE, Ramsköld D, Deng Q, Johnsson P, Michaëlsson J, Frisén J, Sandberg R. “Analysis of allelic expression patterns in clonal somatic cells by single-cell RNA-seq” 2016.
Nat Genet. 48:1430-1435

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. “Fetal CD103+ IL-17-Producing Group 3 Innate Lymphoid Cells Represent the Dominant Lymphocyte Subset in Human Amniotic Fluid” 2016.
J Immunol. 197:3069-3075

Björkström NK, Ljunggren HG, Michaëlsson J. “Emerging insights into natural killer cells in human peripheral tissues” 2016.
Nat Rev Immunol. 16:310-20

Renoux VM, Zriwil A, Peitzsch C, Michaëlsson J, Friberg D, Soneji S, Sitnicka E. “Identification of a Human Natural Killer Cell Lineage-Restricted Progenitor in Fetal and Adult Tissues” 2015.
Immunity 43:394-407

Marquardt N, Ivarsson MA, Blom K, Gonzalez VD, Braun M, Falconer K, Gustafsson R, Fogdell-Hahn A, Sandberg JK, Michaëlsson J. “The Human NK Cell Response to Yellow Fever Virus 17D Is Primarily Governed by NK Cell Differentiation Independently of NK Cell Education” 2015. 
J Immunol. 195:3262-72

Marquardt N, Béziat V, Nyström S, Hengst J, Ivarsson MA, Kekäläinen E, Johansson H, Mjösberg J, Westgren M, Lankisch TO, Wedemeyer H, Ellis EC, Ljunggren HG, Michaëlsson J, Björkström NK. “Cutting edge: identification and characterization of human intrahepatic CD49a+ NK cells” 2015.
J Immunol. 194:2467-71

Ivarsson MA, Loh L, Marquardt N, Kekäläinen E, Berglin L, Björkström NK, Westgren M, Nixon DF, Michaëlsson J. “Differentiation and functional regulation of human fetal NK cells” 2013.
J Clin Invest. 123:3889-901

Blom K, Braun M, Ivarsson MA, Gonzalez VD, Falconer K, Moll M, Ljunggren HG, Michaëlsson J, Sandberg JK. “Temporal dynamics of the primary human T cell response to yellow fever virus 17D as it matures from an effector- to a memory-type response” 2013.  
J Immunol. 190:2150-8.

Fauriat C, Ivarsson MA, Ljunggren HG, Malmberg KJ, Michaëlsson J. ”Education of human natural killer cells by activating killer cell immunoglobulin-like receptors” 2010.
Blood 115:1166-74

Mold JE, Venkatasubrahmanyam S, Burt TD, Michaëlsson J, Rivera JM, Galkina SA, Weinberg K, Stoddart CA, McCune JM. “Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans” 2010.
Science. 330:1695-9

Mold JE, Michaëlsson J, Burt TD, Muench MO, Beckerman KP, Busch MP, Lee TH, Nixon DF, McCune JM. “Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero” 2008.
Science. 322:1562-5

Michaëlsson J, Mold JE, McCune JM, Nixon DF. “Regulation of T cell responses in the developing human fetus” 2006.
J Immunol. 176:5741-8.

Available preprints

Nicole Marquardt, Marlena Scharenberg, Jeffrey E. Mold, Joanna Hård, Eliisa Kekäläinen, Marcus Buggert, Son Nguyen, Jennifer N. Wilson, Mamdoh Al-Ameri, Hans-Gustaf Ljunggren, Jakob Michaëlsson. “High-dimensional analysis reveals a distinct population of adaptive-like tissue-resident NK cells in human lung” 2019. bioRxiv 883785

Jeff E. Mold, Laurent Modolo, Joanna Hård, Margherita Zamboni, Anton J.M. Larsson, Carl-Johan Eriksson, Patrik L. Ståhl, Erik Borgström, Simone Picelli, Björn Reinius, Rickard Sandberg, Pedro Réu, Carlos Talavera-Lopez, Björn Andersson, Kim Blom, Johan K. Sandberg, Franck Picard, Jakob Michaëlsson, Jonas Frisén. “Clonally distinct differentiation trajectories shape CD8+ memory T cell heterogeneity after acute viral infections in humans” 2019.
bioRxiv 832899

A complete list of publications from Jakob Michaëlsson are found at PubMed and Google scholar.

Financial support

We are grateful for our support from the Swedish Research Council, Swedish Cancer Society, Swedish Heart-Lung Foundation, and Karolinska Institutet.