Periodic Reporting for period 4 - EXODUS (Light induced spatially EXact and genetically encoded labeling of immune cells for monitoring of lOng Distance and Ultra-compartment Shuttling during autoimmunity and chronic inflammation)
Reporting period: 2020-03-01 to 2021-05-31
The incidence of autoimmune diseases in modern societies is increasing, and correlative data suggest that the interaction of the immune system with microbiota at barrier tissues might be associated with the initiation and maintenance of autoimmune inflammation at distant sites including the central nervous system (CNS). However, a pathomechanistic understanding of this process is essentially lacking. For example, it is unknown whether autoreactive T cells are primed in the gut lamina propria or gut draining lymph nodes or in other secondary lymphoid tissues like skin draining lymph nodes or the spleen and - in particular for autoimmunity in the CNS - there is limited information whether priming at different sites would imprint different properties in autopathogenic T cells, for instance in terms of their homing capabilities to distinct sites within the CNS. In addition, during advanced autoimmune diseases in the CNS, compartmentalized inflammation within the intrathecal compartment with limited exchange with the systemic immune compartment has been blamed to be the driving force of the disease process. Here, it is unclear whether priming of pathogenic T cells occurs within the intrathecal compartment and which are the most relevant antigen presenting cells at this site.
Autoimmunity in general and CNS autoimmunity in particular target young adults and are not yet curable. Therefore, they deposit a significant personal burden on affected individuals and a significant socioeconomic burden on society. Novel therapeutic approaches aiming at the activation of the immune system at barrier sites have been proposed and some of these novel ideas even try to manipulate the microbiome to eventually modulate immune responses at distant sites. However, due to the substantial gaps in knowledge how immune responses at barrier tissues are "translated" into distant organs such as the CNS, these approaches must be considered as immature.
This is the broader context of the current ERC project. Specifically, the major aims of this project are (1) to identify relevant antigen presenting cells at priming sites of autoreactive T cell, and here we chose to focus on IL-6 producing antigen presenting cells because IL-6 is a non-redundant factor in the generation of tissue pathogenic autoreactive T cells. And (2) to develop provenance mapping systems that would allow us to actually track immune cells from sites of priming to target tissues of autoimmune diseases like the CNS and also to assess the egress of immune cells from affected organs of autoimmune diseases.
Autoimmunity in general and CNS autoimmunity in particular target young adults and are not yet curable. Therefore, they deposit a significant personal burden on affected individuals and a significant socioeconomic burden on society. Novel therapeutic approaches aiming at the activation of the immune system at barrier sites have been proposed and some of these novel ideas even try to manipulate the microbiome to eventually modulate immune responses at distant sites. However, due to the substantial gaps in knowledge how immune responses at barrier tissues are "translated" into distant organs such as the CNS, these approaches must be considered as immature.
This is the broader context of the current ERC project. Specifically, the major aims of this project are (1) to identify relevant antigen presenting cells at priming sites of autoreactive T cell, and here we chose to focus on IL-6 producing antigen presenting cells because IL-6 is a non-redundant factor in the generation of tissue pathogenic autoreactive T cells. And (2) to develop provenance mapping systems that would allow us to actually track immune cells from sites of priming to target tissues of autoimmune diseases like the CNS and also to assess the egress of immune cells from affected organs of autoimmune diseases.
We have generated novel tools to track IL-6 producing cells, and have used these tools to investigate the dynamics and functional relevance of IL-6 production in a variety of immune cell types in the context of autoimmune inflammation in the central nervous system (CNS). In addition, we are now combining this IL-6 reporter system with genetic tools that will allow us to track back the provenance of immune cells that can be recovered from the inflamed CNS. By this means, we will be able to connect spatial information about the provenance of immune cells from sites outside the CNS (either secondary lymphoid tissue or barrier tissues) with their behaviour within the CNS (localization, functional properties, survival).
We have discovered a novel (and unexpected) modality of IL-6 signaling that we call IL-6 cluster signaling. Here, donating cells present the IL-6 molecule via their own IL-6R subunit in trans to receiving cells, which only need to express gp130 (the second subunit of the IL-6 receptor system) in order to respond to IL-6. We found that this modality of IL-6 signaling, which requires close proximity of transmitting and receiving cell, has a major impact on the imprinting of pathogenic properties in autoreactive T cells.
Until the end of the project, we expect to be able to have established fundamentally novel tools to map the spatial provenance of migratory cells (immune cells and non-immune cells) that are found in the CNS or any other parenchymal organ.
Until the end of the project, we expect to be able to have established fundamentally novel tools to map the spatial provenance of migratory cells (immune cells and non-immune cells) that are found in the CNS or any other parenchymal organ.