Four pathways of CD1 antigen presentation to T cells

•Human CD1a, CD1b, CD1c, and CD1d use distinct pathways for trafficking and antigen capture.•CD1a, CD1b and CD1c have inducible expression, yet upstream genetic regulators are unknown.•CD1 antigen binding clefts are defined by locations of named portals where antigens protrude.•CD1b is a structural outlier: it has a large volume cleft, which no known self lipid fully occupies.•CD1-TCR contact follows three general models: 'headgroup discrimination,' 'absence of Interference' and 'CD1 remodeling'.

CD1a, CD1b, CD1c and CD1d proteins migrate through distinct subcellular compartments of antigen presenting cells and so can be considered to take four separate pathways leading to display of lipid antigens to T cell receptors. This review discusses the intersection of CD1 trafficking and lipid antigen loading mechanisms in cells, highlighting key controversies relating to CD1 gene expression, size mismatches between antigens and CD1 binding clefts and unexpected mechanisms of T cell receptor-based recognition.