Main research questions:
- What are the metabolic requirements for DCs to prime and polarize different T cell responses? (project 1,2,3)
- How does the metabolic micro-environment affect the functional properties of dendritic cells and macrophages in cancer, obesity and autoimmune diseases? (Project1, 2, 3, 4)
- How do metabolic sensors AMPK and mTOR shape the T cell priming and polarizing properties of dendritic cells? (project 1)
- Can immune cell metabolism be targeted to reverse immune- and vaccinehyporesponsiveness? (project 4,5)
Methodology and Tools:
- Metabolic flux analysis
- High dimensional flow cytometry
- Single cell metabolic profiling assays
- Untargeted metabolomics
- RNA sequencing
- In vitro culture systems of human DCs and macrophages
- Murine models of infection and cancer with conditional KO mice
Projects
1.Role of metabolic sensors in DC-driven T cell priming & polarization
AMP activated kinase (AMPK) and mechanistic target of rapamycin (mTOR) are cellular metabolic sensors that play a key role in finetuning cellular responses and metabolism to environmental cues and nutrient availability. AMPK is activated under energy stress and promotes catabolic metabolism, while mTOR activation promotes anabolic metabolism during nutrient replete condtions. This project aims to define how nutrient availability in tissues affect the balance between mTOR and AMPK signaling and subsequently the T cell priming function of DCs, in the context of infections, cancer and obesity.
Funding: KWF, NWO
Collaborations: Dr. B. Guigas, Dr. R. Arens, Dr. L. Hawinkels, European Immunometabolism network (EIMN)
2.Role of O-GlcNAcylation in type 2 immune responses
O-GlcNAcylation is a post-translational modification (PTM) in which N-acetylglucosamine (GlcNAc) moieties are reversibly attached to threonine or serine residues of intracellular proteins. It is controlled by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA/MGEA5) that attach or remove GlcNAc from proteins, respectively. It is now clear that O-GlcNAcylation affects various cellular processes including transcription, translation, signal transduction and metabolism. Partly, this is due to interplay with other PTMs such as phosphorylation, which competes for the same target residues. Dysregulated O-GlcNAcylation has been implicated in the pathogenesis of several human diseases including cancer, diabetes and neurodegeneration. While evidence is emerging that this process may also be important in regulating functional properties of myeloid cells, its role in the regulation of macrophages and dendritic cells in the context of Type 2 immune responses as those found during helminth infections or allergic responses is poorly defined. This project aims to define the role of O-glcNAcylation alternative activation of macrophages and Th2 induction by DCs, and to explore whether this pathway could be targeted to shape Type 2 immune responses in therapeutic settings.
Funding: NWO
Collaborations: Prof. Dr. C.H. Hokke (LUMC), Dr. P. van Veelen (LUMC), Dr. F. Ronchese (Malaghan Institute, New Zealand)
3. Development of novel Click-Chemistry based probes to study nutrient uptake at single cell level
Nutrient uptake fuels immune cell metabolism and is therefore critical to immune cell function. However, detailed nutrient uptake analyses have thus far been significantly hampered by the lack of available approaches to faithfully track uptake of nutrients of single cells in vivo that enable one to functionally study metabolism of rare cell populations, such as DC subsets, in situ. Such tools will be central to understanding how nutrients, or the lack thereof, shape the metabolic profile, and consequent function, of immune cells within a given physiological microenvironment. To combat this, our team has recently pioneered the use of single cell-compatible click chemistry to successfully define in vivo glutamine uptake within heterogenous immune populations. This project aims to use bio-orthogonal click-chemistry to develop a multiplex click chemistry-compatible uptake assay for core nutrients glucose, fatty acids and glutamine, as well as methods to combine this technology with modern single-cell analysis platforms. These tools will be utilized to characterize nutrient uptake profiles of DCs in situ following immunization and in the context of cancer, using murine models and human primary tumor samples. This will define the importance of nutrient uptake for DC function in those contexts and explore whether manipulation of nutrient uptake can be used to improve vaccination and anti-tumor immunity.
Funding: NWO
Collaborations: Dr. S van Kasteren (Leiden Institute for Chemistry)
4. Role of altered dendritic cell metabolism in impaired vaccine responses in elderly
Vaccinations have proven to be one of the most successful public health interventions. However, their efficacy is reduced in elderly individuals, which form an ever-growing part of the general population. This signifies the urgent need for developing strategies to improve vaccine responses to reduce the infectious disease burden in these populations. The causes behind the impaired vaccine response are still poorly understood. Intriguingly, recently murine and in vitro studies and finding from my group have revealed aging-associated alterations in metabolism of dendritic cells (DC), the main cellular targets of vaccines. Given the importance of metabolism in shaping DC function, this project aims to map in detail the immunometabolic profiles of DCs in response to vaccination in situ in healthy individuals and how they are disrupted in aged settings following Fine needle aspiration of vaccine draining lymph nodes, with the goal to identify the metabolic disturbances in DCs that can be targeted to improve DC functionality and enhance vaccine responses in elderly.
Funding: LUCID stimulation fund
Collaborations: Dr. S. Jochems (LUMC), Dr. A. Roukens (LUMC)
5. Understanding the mechanisms behind immune- and hyporesponsiveness to malaria vaccines by studying immune cell metabolism
Globally vaccines have prevented 37 million deaths in the last 20 years alone, thereby having a substantial impact on global health. However, the full potential of several vaccines, is hampered by the low and variable efficacy, which is highly associated with the geographical region where the vaccine is administered. This is particularly true for malaria vaccines, which while
highly efficacious when first tested in high income countries, show disappointing results in endemic areas, where it is most needed. In a collaborative effort between multiple international research centers multi-omics technologies will be applied for an in depth immunological and immunometabolic characterization of malaria vaccine cohorts from diverse geographical areas to predict vaccine induced and naturally acquired immunity and to understand malaria vaccine (hypo)responsiveness. The knowledge will build a strong foundation for developing an improved malaria vaccine with high efficacy in malaria endemic areas.
Funding: NIH NIAID consortium grant, Gates Foundation
Collaborations: Prof. Dr. M. Yazdanbakhsh (LUMC)
