Atypical sideways recognition of CD1a by autoreactive gamma delta T cell receptors

T cell receptors are generally thought to contact antigens presented in an end to end configuration. Here the authors show a geometrically alternate sideways mode of recognition of the antigen-presenting molecule CD1a by a gamma delta T cell receptor. CD1a is a monomorphic antigen-presenting molecule on dendritic cells that presents lipids to alpha beta T cells. Whether CD1a represents a ligand for other immune receptors remains unknown. Here we use CD1a tetramers to show that CD1a is a ligand for V delta 1(+) gamma delta T cells. Functional studies suggest that two gamma delta T cell receptors (TCRs) bound CD1a in a lipid-independent manner. The crystal structures of three V gamma 4V delta 1 TCR-CD1a-lipid complexes reveal that the gamma delta TCR binds at the extreme far side and parallel to the long axis of the beta-sheet floor of CD1a's antigen-binding cleft. Here, the gamma delta TCR co-recognises the CD1a heavy chain and beta 2 microglobulin in a manner that is distinct from all other previously observed gamma delta TCR docking modalities. The 'sideways' and lipid antigen independent mode of autoreactive CD1a recognition induces TCR clustering on the cell surface and proximal T cell signalling as measured by CD3 zeta phosphorylation. In contrast with the 'end to end' binding of alpha beta TCRs that typically contact carried antigens, autoreactive gamma delta TCRs support geometrically diverse approaches to CD1a, as well as antigen independent recognition.