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Lipid antigens in intestinal inflammation and tumor development

Final Report Summary - IBDLIPIDS (Lipid antigens in intestinal inflammation and tumor development)

Inflammatory bowel diseases (IBD) are a group of diseases characterized by chronic intestinal inflammation and an increased risk of colorectal cancer. Current treatment of IBD is based on immunosuppression which targets the final steps of the inflammatory process rather than its origin and is associated with significant side effects. There is thus a need for better understanding of disease pathogenesis to develop novel and more efficacious therapies.
Natural killer T (NKT) cells are a subset of T cells that recognize lipid antigens presented by the atypical MHC class I molecule CD1d. NKT cells have central contributions to the pathogenesis of IBD and other immune-mediated diseases, which suggests that interference with lipid antigen presentation and NKT cell activation might provide a novel approach for interference with early steps in the pathogenesis of immune-mediated diseases. However, little is known about the spectrum of lipids associated with CD1d, which limits the ability to therapeutically target lipid antigen presentation. In addition, lipid antigen presentation can elicit different outcomes, ranging from regulatory to inflammatory responses, depending on the cellular origin of CD1d signals. For this reason, the main goals of this project were (i) to provide a better understanding of the cell-type specific effects of CD1d-restricted lipid antigen presentation in intestinal inflammation and carcinogenesis and (ii) to gain insight into the spectrum of CD1d-associated lipids.
We could demonstrate that CD1d plays cell-specific roles in intestinal inflammation. While CD1d in the intestinal epithelium elicits protective effects, bone marrow-derived CD1d promotes inflammation in an NKT cell-dependent manner. These studies suggest that strategies for interference with lipid antigen presentation in IBD will likely require cell-specific approaches for therapeutic targeting. Second, we found that CD1d plays a limited role in intestinal tumor development, with no evidence of contributions of intestinal epithelial or myeloid CD1d to tumor growth, together suggesting a limited value of targeting of CD1d in intestinal tumor development. Third, we could establish engineered CD1d molecules that allow to harvest CD1d from live cells for mass spectrometry-based analysis of associated lipids. These tools will provide the basis for the study of CD1d-associated lipids across different cells and tissues. Fourth, we could show that major non-antigenic cellular sphingolipids such as sphingomyelins play critical roles in the regulation of immunity through binding to CD1d and inhibition of NKT cell activation. Lastly, we contributed to work which demonstrated that endoplasmic reticulum stress shapes the spectrum of CD1d associated lipids, which leads to the activation of NKT cells and promotes sterile inflammation through CD1d-restricted presentation of immunogenic self-lipids.
In conclusion, this ERC-funded project provided major new insight into the contributions of lipid antigens and NKT cells to inflammation in immune-mediated diseases such as IBD and highlighted new pathways amenable to therapeutic targeting.