Lipids in immunometabolism: From lipid handling to lipid antigen presentation and back

Within this thesis we utilized and developed several model systems allowing us to strategically address the different levels of complex interactions and mechanisms. In chapter 2 we use a mixture of FFA’s mimicking the lipid-rich microenvironment of obesity in vitro, co-culturing these now insulin resistant (IR) adipocytes with iNKT cells demonstrated that the adipocyte IR phenotype causes a pro-inflammatory skew in iNKT cell cytokine output, suggesting that cross-talk is an important target for further research. Following this, in chapter 3, we hypothesized that AT-resident immune cells may also be detrimentally affected when exposed to a lipid-rich microenvironment. As LD’s are found in many immune cells perhaps the elevated lipid environment would cause dysfunction in iNKT cells as well, creating a compound effect of dysfunctional communication between adipocytes and iNKT cells. We found iNKT cells are capable of taking up and storing lipids in droplets, even in “lean” conditions making them highly sensitive to their lipid environment as well as their lipid content. These findings highlight the importance of distinguishing between resident immune populations, as AT-resident iNKT cells respond differently to lipid environments compared to other iNKT cells in different locations. In chapter 4 and chapter 5 we show the nuanced nature of Tribbles 3 interactions with the available local partners to deliver site specific action. Chapter 4 addresses the consequences of a global Tribbles 3 knock out, focusing on alterations –including the lipidome– in adipose tissue and adipocytes. We further investigated this in chapter 5 focusing on the change in abundance of mitochondrial specific lipid species Cardiolipins. Here we find that changes in the ultrastructure of mitochondria results better stress tolerance under acute stress. Given its diverse interactions and implications in various diseases, understanding the interactions and functions in specific cellular contexts, such as Tribbles 3’s role in adipose tissue lipidome modulation, offers potential avenues for targeted therapeutic interventions. The intricate interplay between local and global lipidomes and regulators or disruptors is an area of growing interest, as these conserved mechanisms appear to converge on crucial cellular processes. In chapter 5 we present our data which suggests that pseudokinase Tribbles 3 may participate in location specific lipid metabolism and lipid signaling pathways, modulating the lipidome and thereby influencing responses to external cues. In chapter 6 part a we reflect on the available adipose tissue model systems and the limitations they pose, showing their usefulness in specific contexts depending on the research question,. Finishing with chapter 6 part b, we review how lipidome species ratios may impact the local and global action of adipose resident iNKT cells.