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Elucidating the role of liver resident Kupffer cells in the regulation of the immune responses to intestinal antigens

Periodic Reporting for period 1 - KCs and Gut Antigens (Elucidating the role of liver resident Kupffer cells in the regulation of the immune responses to intestinal antigens)

Reporting period: 2015-05-01 to 2017-04-30

Food allergies and inflammatory bowel diseases are increasing health problems in industrialized countries. These diseases result from an abnormality in the way the immune system reacts to harmless materials in our gut such as foods and friendly bacteria. To be able to design new and improved ways of treating or preventing these disorders, we must first understand the processes that usually prevent them in healthy individuals. The liver drains all the blood coming from the intestine and has long been thought to be important in controlling immune responses to these materials. However, the precise cell(s) involved, or the underlying molecular mechanisms are still unknown. This project aimed to address this gap in our knowledge by generating and applying new methods to study Kupffer cells (KCs), which are not only the most abundant immune cells in the liver but also the first immune cells to be in contact with materials entering the liver from the intestine as they reside in the blood flow in the liver sinusoids. We also aimed to assess how KCs influence the other immune cells involved in instructing immune responses to such agents.
Through this fellowship, we have greatly enhanced our understanding of KC biology and more generally macrophage and dendritic cell (DC) biology, the key cell types, present in almost all organs, which acquire and cue the immune system to respond appropriately to foreign and host agents. We have shown that, contrary to previous opinion, cellular origin is irrelevant in defining KCs but rather that the local environment is crucial in programming these macrophages. This is crucial to our understanding of macrophage function. Moreover, this finding opens the door to monocyte therapy to replace defective macrophage populations such as those that may respond inappropriately to intestinally-derived agents (antigens). We have also developed precise methods to identify and isolate different immune cells which respond to such antigens from mice and men, a process crucial to our better understanding of the specific functions of each of these cell types. Furthermore, we have shown that KCs are not strictly required for the generation of oral tolerance, but that they function in modulating the different immune responses to orally-administered agents.

The main findings from this project have been published (see below) and either have been or will be presented at an array of scientific meetings (see below). In addition, we are communicating the results to the public through participation in the Institute’s Biotechday, which will be held this year in October on the theme “Goed om (w)eten” (Good to know/eat).

Publications:
- CL Scott et al., Bone marrow derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nature Communications. 2016. IF 11.329
- M Guilliams* and CL Scott*. Does Niche competition determine the origin of tissue-resident macrophages? Nature Reviews Immunology. 2017. IF 39.416 *co-corresponding authors.
- M Guilliams*, CA Dutertre*, CL Scott* et al., Unsupervised high dimensional analysis aligns dendritic cells across tissues and species. Immunity 2016. IF 24.082 *co-first authors
- CL Scott*, B Soen* et al., The transcription factor Zeb2 regulates the development of conventional and plasmacytoid DCs by repressing Id2. JEM 2016. IF 11.240 *co-first authors
- D Sichien, BN Lambrecht, M Guilliams & CL Scott. Development of conventional dendritic cells: from common bone marrow progenitors to multiple subsets in peripheral tissues. Mucosal Immunology. 2017. IF 7.374.
- D Sichien, CL Scott et al., IRF8 transcription factor controls survival and function of terminally differentiated conventional and plasmacytoid DCs respectively. Immunity. 2016. IF 24.082
- K Van Der Borght, CL Scott et al., Myocardial Infarction primes autoreactive T cells through activation of dendritic cells. Cell Reports. 2017. IF 7.870.
- L Van de Laar et al., Yolk-sac macrophages, foetal liver and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages. Immunity. 2016. IF 24.082. (Middle author)
- CC Bain et al., Long lived self-renewing bone marrow derived macrophages displace embryo-derived cells to inhabit adult serous cavities. Nature Communications. 2016. IF 11.329. (Middle author)

Conference Attendance:

Invited Talks
1. CFCD 2017 Paris, France - http://www.cfcd.fr/meeting/program.html
2. SFI 2017 Reims, France - http://www.alphavisa.com/sfi/2016/
3. ESCI 2017 Genoa, Italy - http://esci2017.grupposymposia.it
4. VIB Macrophage Symposium 2017 Ghent Belgium
5. Immunological Disease and Translation Resolution Summit 2016, Shanghai 2016
6. Ghent Gut Immunology Group Meeting 2015, Ghent Belgium

Selected Short Talks
1. International Dendritic Cell Symposium (DC2016) – Shanghai
2. International Congress of Immunology (ICI) 2016 – Melbourne
3. 16th International Congress of Mucosal Immunology (ICMI) 2015 – Berlin
4. Dendritic Cells and Macrophages Reunited 2015 – Keystone

Posters
1. Mononuclear Phagocytes in Health, Immune Defense and Disease 2017 – Keystone
When this project began, we could not specifically identify and isolate the different macrophage and dendritic cell subsets in a conserved way across tissues and species. This thus led to different groups identifying these cells according to their preferred protocols, making it difficult to compare results across labs. Having, as part of this project, developed a conserved method for the unsupervised analysis of Dendritic cell subsets (Guilliams, Dutertre, Scott et al. 2016, Immunity) and having identified methods to distinguish bona fide KCs from other hepatic macrophages (Scott et al, 2016. Nature Communications) we can now align these protocols across labs. Indeed, the publication in Immunity is in the top 10 downloaded papers from 2016 highlighting the interest across the field in such a strategy.
Our analysis demonstrating that genuine KCs can be derived from bone marrow monocytes rather than embryonic progenitors (Scott et al, 2016. Nature Communications) and work I contributed to highlighting that this is also true for alveolar macrophages in the lung (Van de Laar et al., 2016. Immunity) opens the door for monocyte based cellular therapy whereby defective macrophage populations can be replaced by administering monocytes in the right environment. Monocytes can be easily isolated from the blood making this a feasible potential strategy in the future.
With the new tools generated as part of this fellowship, we have also generated some more preliminary data regarding the role of KCs in mounting immune responses to orally administered antigens and local factors emanating from the gut. Based on this, we have secured further funding to continue this research which we hope will further extend our knowledge of how the immune systems responds to intestinal antigens and how we can begin to manipulate the system to prevent/treat disease including food intolerances.
SEM Image of a Murine Kupffer Cell