Tim Willinger group - Understand Fundamental Immune Mechanisms to Develop New Treatments for Lung Diseases

About our research

My research group studies immune responses with a focus on the lung. The lung is a vital organ that is directly exposed to the outside world and therefore a common site of infection, chronic inflammation, and cancer. Both acute and chronic lung injury are common and often mediated by the immune system.

We want to understand how the immune system helps maintain healthy lung function and how disturbed immune function causes lung inflammation. Our studies focus on macrophages, tissue-resident immune cells that carry out specialized functions to maintain organ homeostasis and promote barrier immunity. To make our studies relevant to humans, I have developed innovative models that allow us to investigate the cells and function of the human immune system in vivo. Our long-term aim is to contribute to the development of macrophage-based treatments for lung diseases.

Group leader

Tim Willinger joined CIM in 2015 to establish his research group at Karolinska Institutet.

Tim did his scientific training in immunology at Oxford and Yale University with Andrew McMichael and Richard Flavell. During his postdoc, he developed novel experimental models to study the human immune system in vivo (Cell Host Microbe 2010, PNAS 2011, Trends Immunol 2011, Nat Biotechnol 2014). He also identified molecular mechanisms that regulate T lymphocyte homeostasis and migration (PNAS 2012, JEM 2014, PNAS 2015). He was awarded a faculty-funded career position as Senior Researcher in 2018 and became a Docent in Immunology in 2020.

He enjoys all intellectual things, as well as gardening and traveling.

Group members

Natalie has been working at Karolinska Institutet/Karolinska Sjukhuset for several years. She likes to spend her spare time either in the stable or the gym. She also loves to watch movies, another big hobby of her.

Rong received her Ph.D. degree from the Institut Pasteur of Shanghai, Chinese Academy of Sciences in 2022. During her Ph.D., she focused on the study of intestinal mucosal immunity.

In her spare time, she enjoys traveling and photography.

Laura Bub received her Master's Degree in Biology with a specialization in biomedicine at the Justus-Liebig University in Germany. She completed her master's thesis at Uppsala University through Erasmus+ working on the effect of mast cell proteases on breast cancer.

In her free time, she enjoys reading, baking and hanging out at the stables.

Previous group members

• Helen Jongsma Wallin, Lab technician
• Hana Kammoun, Postdoc (Marie Curie Fellow)
• Emma Ringqvist, Postdoc
• Imran Mohammad, Postdoc
• Yu Gao, Postdoc
• Johanna Emgård, PhD student
• Elza Evren, PhD student
• Arlisa Alisjahbana, PhD student
• Linda Moet, Master student
• Yiqi Huang, Master student
• Inés Có Rives, Bachelor student (ERASMUS)

Collaborations

International

• Richard Flavell (Yale University, USA)
• James Di Santo (Pasteur Institutet, France)
• Bart Lambrecht (Ghent University, Belgium)
• João Pereira (Yale University, USA)
• Andrea Reboldi (University of Massachusetts, USA)
• Andreas Schlitzer (University of Bonn, Germany)

Karolinska Institutet

• Niklas Björkström Center for Infectious Medicine, Department of Medicine, Huddinge
• Apostolos Bossios Department of Respiratory Medicine, Huddinge
• Carmen Gerlach (Department of Medicine, Solna)
• Anna Smed Sörensen Department of Medicine, Solna
• Eduardo Villablanca (Department of Medicine, Solna)
• Fredrik Wermeling (Department of Medicine, Solna)

Projects

Development and function of lung macrophages

Macrophages are the most abundant immune cells in the lung. Due to their strategic location, they protect us from airborne pathogens, while performing tissue repair after injury or infection. However, not much is known about the development and function of lung macrophages in humans. To overcome this limitation, we have created a unique model to study human macrophages in vivo. Using this model, we have recently discovered how human blood monocytes migrate and become distinct types of lung macrophages. Blood monocyte-derived macrophages are relevant in many lung diseases, including COVID-19. In addition, we have identified the fetal precursor of human lung macrophages and how cell origin impacts the function of human lung macrophages

KI News — 30 December 2020: New research may explain severe virus attacks on the lungs

KI News —  12 January 2022: New study reveals how the lung's immune cells develop after birth

Immune sensing of lung injury

We address the fundamental question of how the immune system senses tissue damage and how this affects the outcome of lung injury. We focus on G protein-coupled receptors, an important receptor family that allows cells to respond to extracellular signals, such as metabolites, hormones, and chemoattractants. One such receptor expressed in immune cells is GPR183, a cell surface receptor for hydroxylated cholesterol metabolites, called oxysterols. We discovered that oxysterols recognized through GPR183 guide the movement of specific immune cells and promote the formation of lymphoid tissue in the gut. Our study suggests a new possible treatment for inflammatory bowel disease.

KI News — 16 January 2018: Oxysterols guide gut immune cells and are involved in inflammatory bowel disease

Selected publications

1. A single-cell map of vascular and tissue lymphocytes identifies proliferative TCF-1+ human innate lymphoid cells.
   Gao Y, Alisjahbana A, Boey DZH, Mohammad I, Sleiers N, Dahlin JS, Willinger T
   Front Immunol 2022 ;13():902881
    
2. CD116+ fetal precursors migrate to the perinatal lung and give rise to human alveolar macrophages.
   Evren E, Ringqvist E, Doisne JM, Thaller A, Sleiers N, Flavell RA, Di Santo JP, Willinger T
   J Exp Med 2022 02;219(2):
    
3. CD5 Surface Expression Marks Intravascular Human Innate Lymphoid Cells That Have a Distinct Ontogeny and Migrate to the Lung.
   Alisjahbana A, Gao Y, Sleiers N, Evren E, Brownlie D, von Kries A, Jorns C, Marquardt N, Michaëlsson J, Willinger T. Front Immunol 2021 ;12():752104
    
4. Continuous human uterine NK cell differentiation in response to endometrial regeneration and pregnancy.
   Strunz B, Bister J, Jönsson H, Filipovic I, Crona-Guterstam Y, Kvedaraite E, Sleiers N, Dumitrescu B, Brännström M, Lentini A, Reinius B, Cornillet M, Willinger T, Gidlöf S, Hamilton RS, Ivarsson MA, Björkström NK. Sci Immunol 2021 02;6(56):
    
5. 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
    
6. Origin and ontogeny of lung macrophages: from mice to humans.
   Evren E, Ringqvist E, Willinger T Immunology 2020 06;160(2):126-138
    
7. Metabolite Sensing by Colonic ILC3s: How Far Is Too Ffar2 Go?
   Alisjahbana A, Willinger T. Immunity 2019 11;51(5):786-788
    
8. Antigen-presenting ILC3 regulate T cell-dependent IgA responses to colonic mucosal bacteria.
   Melo-Gonzalez F, Kammoun H, Evren E, Dutton EE, Papadopoulou M, Bradford BM, Tanes C, Fardus-Reid F, Swann JR, Bittinger K, Mabbott NA, Vallance BA, Willinger T, Withers DR, Hepworth MR. J Exp Med 2019 04;216(4):728-742
    
9. Oxysterol Sensing through the Receptor GPR183 Promotes the Lymphoid-Tissue-Inducing Function of Innate Lymphoid Cells and Colonic Inflammation.
   Emgård J, Kammoun H, García-Cassani B, Chesné J, Parigi SM, Jacob JM, Cheng HW, Evren E, Das S, Czarnewski P, Sleiers N, Melo-Gonzalez F, Kvedaraite E, Svensson M, Scandella E, Hepworth MR, Huber S, Ludewig B, Peduto L, Villablanca EJ, Veiga-Fernandes H, Pereira JP, Flavell RA, Willinger T. Immunity 2018 01;48(1):120-132.e8
    
10. Development and function of human innate immune cells in a humanized mouse model.
    Rongvaux A, Willinger T, Martinek J, Strowig T, Gearty SV, Teichmann LL, Saito Y, Marches F, Halene S, Palucka AK, Manz MG, Flavell RA
    Nat Biotechnol 2014 Apr;32(4):364-72