Studying Mucosal Immunity and Inflammation In Vivo

My research group studies immune responses in mucosal tissues with a focus on the lung. We want to understand how the immune system helps maintain healthy organ function and how disturbed immune function causes chronic tissue inflammation.

Willinger Group. Photo by Tiphaine Parrot
Photo: Tiphaine Parrot

Inflammatory diseases of the lung are very common, such as coronavirus disease 19 (COVID-19) and chronic obstructive pulmonary disease (COPD). However, today no cure is available for these important human diseases.

Our studies focus on two types of tissue-resident immune cells that carry out specialized functions to maintain organ homeostasis: Macrophages and innate lymphoid cells (ILCs). These cells sense and respond to signals from their environment, such as microbes, dietary factors, and metabolites. To make our studies relevant to humans, we have developed innovative models that allow us to study the cells and function of the human immune system in vivo.

Twitter: @WillingerLab


Projects

Development and function of human 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 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017589/). Using this model, we have recently discovered how human blood monocytes migrate and become distinct types of lung macrophages (https://www.cell.com/immunity/fulltext/S1074-7613(20)30531-8). Blood monocyte-derived macrophages are relevant in many lung diseases, including COVID-19 (KI Press Release: https://news.ki.se/new-research-may-explain-severe-virus-attacks-on-the-lungs).

Innate lymphoid cell migration

ILCs are a recently described family of immune cells that are enriched in tissues interacting with the outside world. We are particularly interested in how ILCs migrate within the body and to sites of inflammation. We have recently discovered that cholesterol metabolites (so-called oxysterols) guide the movement of ILCs and promote the formation of lymphoid tissue in the large intestine. Article in Immunity  
Our study suggests a new possible treatment for inflammatory bowel disease (KI Press Release: http://ki.se/nyheter/oxysteroler-leder-tarmens-immunceller-och-ar-inblandade-i-inflammatorisk-tarmsjukdom).


Funding

  • Karolinska Institutet (Faculty-funded position as Senior Researcher/Forskare)
  • Swedish Research Council (Vetenskapsrådet)
  • Center for Innovative Medicine (CIMED)/Region Stockholm
  • Cancerfonden
  • Swedish Heart-Lung Foundation


Collaborations

International

Richard Flavell (Yale University, USA)
James Di Santo (Pasteur Institutet, France)

At Karolinska Institutet

Niklas Björkström (Center for Infectious Medicine)
Apostolos Bossios (Department of Respiratory Medicine, Huddinge)
Joakim Dahlin (Department of Medicine, Solna)
Mikael Karlsson (Department of Microbiology, Tumor and Cell Biology)
Jakob Michaëlsson (Center for Infectious Medicine)
Anna Smed Sörensen (Department of Medicine, Solna)

Members

Tim Willinger

MD, PhD, Group Leader/Associate Professor

He 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). In July 2015, he joined the Center for Infectious Medicine to establish his research group at Karolinska Institutet. 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.

Natalie Sleiers

Laboratory technician

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.

Elza Evren

PhD student

Elza received her Master’s Degree in Immunology from University Pierre and Marie Curie, France, in 2016. She did her master’s thesis in Harvard Medical School where she studied poly-N-acetyl-glucosamine, a bacterial capsule polysaccharide that provides a potentially broad-spectrum target for vaccination. She is fond of travelling, exploring new cultures and learning from past stories.

Arlisa Alisjahbana

PhD student

Arlisa is in her final year of the Master Program in Biomedicine at KI, and is currently studying human lung ILCs for her Master thesis. Before coming to KI, she worked with tuberculosis diagnostic methods in the TB-HIV Research Center at Universitas

Previous members

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


Selected publications

Distinct developmental pathways from blood monocytes generate human lung macrophage diversity.
Evren E, Ringqvist E, Tripathi KP, Sleiers N, Rives IC, Alisjahbana A, et al
Immunity 2020 Dec;():

Origin and ontogeny of lung macrophages: from mice to humans.
Evren E, Ringqvist E, Willinger T
Immunology 2020 06;160(2):126-138

Human macrophages and innate lymphoid cells: Tissue-resident innate immunity in humanized mice.
Alisjahbana A, Mohammad I, Gao Y, Evren E, Ringqvist E, Willinger T
Biochem Pharmacol 2020 04;174():113672

Metabolic Control of Innate Lymphoid Cell Migration.
Willinger T
Front Immunol 2019 ;10():2010

Oxysterols in intestinal immunity and inflammation.
Willinger T
J Intern Med 2019 04;285(4):367-380

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, et al
J. Exp. Med. 2019 Apr;216(4):728-742

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, et al
Immunity 2018 01;48(1):120-132.e8

Dynamin 2-dependent endocytosis sustains T-cell receptor signaling and drives metabolic reprogramming in T lymphocytes.
Willinger T, Staron M, Ferguson SM, De Camilli P, Flavell RA
Proc. Natl. Acad. Sci. U.S.A. 2015 Apr;112(14):4423-8

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, et al
Nat. Biotechnol. 2014 Apr;32(4):364-72

Dynamin 2-dependent endocytosis is required for sustained S1PR1 signaling.
Willinger T, Ferguson SM, Pereira JP, De Camilli P, Flavell RA
J. Exp. Med. 2014 Apr;211(4):685-700

Human hemato-lymphoid system mice: current use and future potential for medicine.
Rongvaux A, Takizawa H, Strowig T, Willinger T, Eynon EE, Flavell RA, et al
Annu. Rev. Immunol. 2013 ;31():635-674

Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasis.
Willinger T, Flavell RA
Proc. Natl. Acad. Sci. U.S.A. 2012 May;109(22):8670-5

Improving human hemato-lymphoid-system mice by cytokine knock-in gene replacement.
Willinger T, Rongvaux A, Strowig T, Manz MG, Flavell RA
Trends Immunol. 2011 Jul;32(7):321-7

Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung.
Willinger T, Rongvaux A, Takizawa H, Yancopoulos GD, Valenzuela DM, Murphy AJ, et al
Proc. Natl. Acad. Sci. U.S.A. 2011 Feb;108(6):2390-5

Human thrombopoietin knockin mice efficiently support human hematopoiesis in vivo.
Rongvaux A, Willinger T, Takizawa H, Rathinam C, Auerbach W, Murphy AJ, et al
Proc. Natl. Acad. Sci. U.S.A. 2011 Feb;108(6):2378-83

A mouse model for the human pathogen Salmonella typhi.
Song J, Willinger T, Rongvaux A, Eynon EE, Stevens S, Manz MG, et al
Cell Host Microbe 2010 Oct;8(4):369-76


Open positions

We are looking for talented and highly motivated students and postdocs to join our research group. To apply, submit cover letter, CV with publication list, and contact information of three references to the group leader Tim Willinger (tim.willinger@ki.se).