CD1 lipidomes reveal lipid-binding motifs and size-based antigen-display mechanisms

• Published in: Cell 2023-10, Vol.186 (21), p.4583-4596.e13
• Main Authors: Huang, Shouxiong, Shahine, Adam, Cheng, Tan-Yun, Chen, Yi-Ling, Ng, Soo Weei, Balaji, Gautham R., Farquhar, Rachel, Gras, Stephanie, Hardman, Clare S., Altman, John D., Tahiri, Nabil, Minnaard, Adriaan J., Ogg, Graham S., Mayfield, Jacob A., Rossjohn, Jamie, Moody, D. Branch
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Antigen Presentation; antigen processing; Antigens, CD1 - chemistry; Antigens, CD1 - metabolism; CD1; dendritic cells; Humans; Lipidomics; Lipids - chemistry; major histocompatibility complex; sphingolipids; T cell receptor; T cells; T-Lymphocytes
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2023.08.022

The CD1 system binds lipid antigens for display to T cells. Here, we solved lipidomes for the four human CD1 antigen-presenting molecules, providing a map of self-lipid display. Answering a basic question, the detection of >2,000 CD1-lipid complexes demonstrates broad presentation of self-sphingolipids and phospholipids. Whereas peptide antigens are chemically processed, many lipids are presented in an unaltered form. However, each type of CD1 protein differentially edits the self-lipidome to show distinct capture motifs based on lipid length and chemical composition, suggesting general antigen display mechanisms. For CD1a and CD1d, lipid size matches the CD1 cleft volume. CD1c cleft size is more variable, and CD1b is the outlier, where ligands and clefts show an extreme size mismatch that is explained by uniformly seating two small lipids in one cleft. Furthermore, the list of compounds that comprise the integrated CD1 lipidome supports the ongoing discovery of lipid blockers and antigens for T cells. [Display omitted] •Human CD1 antigen-presenting molecules display >2,000 cellular self-lipids to T cells•Cellular CD1 proteins edit the self-lipidome by selectively capturing certain lipids•Unlike MHC-peptide complexes, CD1 often presents lipids in an unprocessed form•Antigenic capture patterns of each CD1 protein type differ in lipid size, stoichiometry, and chemical structure Antigen presentation to T cells is often studied in the context of proteins. Analyses of nearly 2,000 distinct human CD1 antigen complexes demonstrate broad sampling of self-cellular lipids for display to T cells, where each CD1 protein captures lipid ligands that differ in size, stoichiometry, and chemical structure.these general lipid motifs can be compared to lipids that contribute to disease, providing new biomedical insights.