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A novel physiological role for IRE1 and RIDD..., maintaining the balance between tolerance and immunity?

Periodic Reporting for period 3 - DCRIDDLE (A novel physiological role for IRE1 and RIDD..., maintaining the balance between tolerance and immunity?)

Período documentado: 2022-02-01 hasta 2023-07-31

Dendritic cells (DCs) play a crucial role as gatekeepers of the immune system, coordinating the balance between protective immunity and tolerance to self-antigens. They enter peripheral tissues as immature (resting) DCs, looking for antigens to grab. Once they’ve acquired an antigen, they mature and migrate to the lymph node to present the antigen to naïve T cells. Depending on how a DC perceives the antigen (i.e. as danger or self-antigen), they will mature in an immunogenic respectively tolerogenic manner, which will steer the ensuing T cell response into protective immunity or tolerance. The signals driving immunogenic maturation of DCs are fairly well characterized thanks to the discovery of Toll like receptors and other pattern recognition receptors. On the contrary, the signals driving tolerogenic maturation remain as yet unknown. This is a highly relevant question as the proper maturation state of the DC (immunogenic versus tolerogenic) is absolutely essential to avoid autoimmunity or enable tumor cell killing.
By serendipity, our lab found a role for a sensor of the unfolded protein response, IRE1, in tolerogenic DC maturation. This made us wonder what are the pathways driving tolerogenic DC maturation and how a conserved protein like IRE1 could fit in this process. It led us to uncover a link between apoptotic cell engulfment, regulation of cholesterol metabolism, tolerogenic DC maturation and IRE1, and clearly expanded the function of IRE1 beyond its well-established role in protein folding.
Since the beginning of the project we gained many new insights in tolerogenic DC maturation, which led to unexpected novel applications to induce tolerance in vivo against autoantigens and desensitize our immune system against allergens. All these findings are currently further under investigation and might have broad societal impact to find novel therapies against autoimmune disorders and/or allergies.
In the first 2,5 years of this project, we mainly tried to confirm and extend the findings that formed the basis of our proposal. In a large-scale RNA sequencing (RNASeq) effort performed before the start of the project, we found indications that activation of the IRE1 signaling branch in dendritic cells (DCs) was linked to apoptotic cell engulfment, cholesterol efflux and DC maturation. All these RNASeq data were confirmed by complementary methods and functionally validated. By using mouse models in which DCs are deficient for IRE1 and/or its downstream target XBP1, we could show that loss of IRE1 leads to a block in apoptotic cell engulfment, defects in cholesterol efflux and a profound defect in DC maturation in steady state condition. We also found that activation of the IRE1 signaling branch correlated with increasing engulfment capacity and increasing levels of cholesterol inside the cell, and was markedly lower in DCs that could not take up any apoptotic cell. This strongly suggested that the trigger for activation of the IRE1 signaling branch in DCs was the influx of lipids such as cholesterol, which is in line with earlier findings on lipid triggered activation of the UPR.
We postulate that IRE1 is needed for sensing the influx of cholesterol and for launching a cholesterol efflux program in DCs, although this remains to be formally demonstrated.

Since loss of IRE1 abrogates homeostatic cDC1 maturation, we now had a tool to interrogate DC homeostatic maturation pathways and over the last year we strongly investigated in novel technologies to study which pathways coordinate the DC maturation program in steady state. Again, genes coupled to cholesterol metabolism stood out and we confirmed that cDC1 maturation in steady state is linked to profound changes in cholesterol metabolism. This was unique to cDC1s and associated with their capacity to engulf apoptotic cells, the main trigger to launch maturation.
It led us to investigate and dissect in more detail pathways of homeostatic and immunogenic maturation using novel technologies. This key question (“what defines the difference between tolerogenic and immunogenic mature DCs”), and how can we apply this knowledge to clinical translation now forms the core research question of my lab, with several people dedicated to it.
While we started off by trying to understand the role of a sensor of the unfolded protein response in dendritic cell biology, the project swiftly moved to a much more general question, i.e. what drives tolerogenic maturation versus immunogenic DC maturation, and how does this affect the ensuing immune response.
The last year we worked as much on pathways driving homeostatic maturation in wild type mice as we did in mice in which the IRE1 pathway is abrogated, and the project clearly split in different branches in my lab.
This brought our focus much more into an area with direct clinical implications. We discovered novel pathways that are important for triggering tolerance and found a way to apply this in vivo. We are currently setting up assays to investigate whether we can use these novel insights to induce tolerance against known antigens in autoimmune disease and/or desensitize our immune system against known allergens.
This is all work in progress that is now being followed up in collaboration with tech transfer units from our institute, and we are eager to pursue this novel research line on potential clinical applications of the project in the coming years, though originally this was not immediately envisioned.
At the more fundamental level, we are working hard to gain more mechanistical insights in the precise role of IRE1 in the DC maturation program and are currently focusing on the role of its endonuclease domain. Finally, a postdoc that will start in 2022 will start addressing the role of IRE1 in viral models.