CD1 research often focuses on finding new bacterial lipid antigens. However, autoreactivity has frequently been detected in the CD1 system. For CD1a, small headless lipids permit docking of autoreactive T cell receptors (TCRs) that bind CD1a but not the carried lipid. This ‘absence of interference’ mechanism broadly predicts features of antigen recognition: low structural specificity for the antigen carried, TCR binding to CD1 proteins carrying many diverse lipids and lipid ligands with small head groups. For CD1b and CD1d, most known TCRs show direct contact with phospholipid and glycolipid head groups that protrude from the groove. The ‘head group’ recognition model predicts high specificity for one type of lipid ligand that has a defined hydrophilic head group.

Owing to the small number of known self antigens and the lack of any ternary crystal structures, it is currently unknown whether CD1c uses one or both of these two antigen recognition mechanisms. We isolated polyclonal T cells from a healthy donor using CD1c tetramers loaded with the small, non-polar model lipid, monoacylglycerol (MAG). Several CD1c-MAG tetramer-positive subpopulations also bound CD1c tetramers that carried diverse endogenous self ligands (CD1c-endo). An IFN-y ELISPOT assay showed that CD1c-expressing antigen presenting cells activated the isolated T cells with or without the presence of MAG, but CD1a or CD1b expressing antigen presenting cells did not, confirming CD1c autoreactivity. These results demonstrate the low specificity for multiple self ligands, which are the functional hallmarks of ‘absence of interference.’ Further we detect CD1c-endo tetramer staining on T cells in many human blood donors, suggesting that this recognition pattern is common. Overall, this work identifies a new self antigen for the CD1c system and points toward broad use of a mechanism that shows an absolute requirement for CD1c but low specificity for the self lipid carried.