X-TALK · Investigation of the cross-talk between innate and adaptive immunity
FP7 — People (Marie Curie Actions)
- Duration
- 2014-01-01 → 2017-12-31
- EU contribution
- €100,000
- Participants
- 1
- Scheme
- MC-CIG
Lines connect the coordinator with its partners.
Results in brief
Investigation of the cross-talk between innate and adaptive immunity
The vertebrate immune system has long been thought to encompass two independent arms: innate immunity, providing the first line of defense, and adaptive immunity, triggered later and responsible for immunological memory. However, there is now cumulative evidence that these two arms are linked and modulate each other. Yet several of the mechanisms underlying the communication pathways between innate and adaptive immune cells are still elusive. The goal of this project was to investigate how two defined innate immune cell types may differentially regulate adaptive immune responses. In particular, we have used different mouse models to investigate the function of plasmacytoid dendritic cells (pDCs) and/or natural killer (NK) cells – both innate immune effectors – for the priming of antigen-specific T cells. We demonstrated the role of pDCs in modulating the activation of NK and T cells, in dependence on molecules involved in pathogen sensing. In addition, we have revealed a novel, non-apoptotic function of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) for the regulation of NK cells. We have also showed that this new pathway is relevant for the control of the adaptive immune response and the resolution of viral infection. A manuscript on this study has been submitted for peer review. Taken together, our research has uncovered novel immunomodulatory mechanisms involved in pathogen control, tumor surveillance and immunopathology, which are of clinical relevance. In addition to this scientific progress, I have established a fully functional laboratory, currently comprising 1 postdoctoral fellow, 2 PhD students and 1 technician – all supported by third party money – as well as 1 BSc student and another technician (supported by my institute). Since the start of the X-talk project, I have raised a total of 1.7 million CHF (ca. 1.4 million EUR) in direct funding for my research. I have also received 1 equipment grant and my staff were able to secure several prizes and fellowships. I have built a solid scientific network for collaborations with several groups and clinicians in Switzerland as well as with industrial partners. I am a regular lecturer of classes, tutorials and practical workshops for medical and biology students. I also act as coordinator and organizer of a course on histology and general pathology for biomedical and cell biology students. I supervise BSc, MSc and PhD students and am a member of the Expert Commission of the Graduate School for Cellular and Biomedical Sciences of the University of Bern, in which function I have been a mentor of 15 and co-advisor of 4 PhD students. I also acted as an external expert for 3 PhD theses. So far, I have supervised until successful completion 2 BSc theses, 5 MSc theses and 2 PhD theses. I currently supervise 2 PhD theses and obtained my “Habilitation” in 2016. Lastly, I recently published 4 peer-reviewed research articles and 2 peer-reviewed reviews as senior author. My group has a website (German and English), with a short lay summary of our research focuses, including the current project: www.pathology.unibe.ch/research/research_groups/group_krebs/
Data: CORDIS, © European Union
Project objective
The vertebrate immune system has long been considered as a bipartite entity encompassing two independent and isolated arms: innate immunity, providing the first line of defense, and adaptive immunity, responsible for memory. Recent evidence suggests that, in addition to their undisputed role in innate immunity, natural killer (NK) cells and plasmacytoid dendritic cells (pDCs) are important contributors to adaptive immune responses. Yet the mechanisms underlying these cellular interactions are still obscure.Lately, we could demonstrate a key role for NK cells in the initiation of adaptive immunity by describing a novel pathway harnessing NK cell cytotoxicity for robust T and B cell priming. Interestingly, this sterile inflammatory response was found to be entirely abrogated in mice lacking Toll like receptor (TLR) signaling. As TLRs also sense commensal bacteria, we propose to use germ-free mice to address the role of the normal flora in this sterile pathway induced by NK cells (Aim 1).Using a new mouse model allowing unbiased assessment of plasmacytoid dendritic cell (pDC) function, we have preliminary data suggesting that in sterile conditions pDCs negatively modulate NK cells and the subsequent priming of adaptive immune effectors. In apparent conflict with these findings, we observed that pDC deficiency in a model of chronic virus infection leads to defective priming of T cells. Such reduced T cell response was preceded by a substantial decrease in cytokine production, most likely as a consequence of diminished NK cell activity. We want to mechanistically address these unexpected and opposite outcomes that are possibly contingent on the nature of the inflammatory environment (Aim 2).Therefore, by providing a deeper insight into the routes of communication used by effectors of the innate and adaptive immunity, our investigation may reveal novel strategies for the immune–modulation of infections, tumor surveillance or autoimmune diseases.
Original text from CORDIS.
Participants
- UNIVERSITAET BERN · BernCoordinatorSwitzerland
Links
Data: CORDIS, © European Union