Atypical sideways recognition of CD1a by autoreactive γδ T cell receptors

• Published in: Nature communications Vol. 13; no. 1; pp. 3872 - 15
• Main Authors: Wegrecki, Marcin, Ocampo, Tonatiuh A., Gunasinghe, Sachith D., von Borstel, Anouk, Tin, Shin Yi, Reijneveld, Josephine F., Cao, Thinh-Phat, Gully, Benjamin S., Le Nours, Jérôme, Moody, D. Branch, Van Rhijn, Ildiko, Rossjohn, Jamie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.07.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/1619/554/1775; 631/250/21; 631/250/262; 631/535/1266; 82/103; Antigens; Binding; Cell surface; Clustering; Crystal structure; Dendritic cells; Humanities and Social Sciences; Ligands; Lipids; Lipids - analysis; Lymphocytes; Lymphocytes T; multidisciplinary; Phosphorylation; Receptors; Receptors, Antigen, T-Cell, gamma-delta - metabolism; Recognition; Science; Science (multidisciplinary); T cell receptors; T-Lymphocytes
• DOI: 10.1038/s41467-022-31443-9
• ISSN: 2041-1723

CD1a is a monomorphic antigen-presenting molecule on dendritic cells that presents lipids to αβ 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 Vδ1 + γδ T cells. Functional studies suggest that two γδ T cell receptors (TCRs) bound CD1a in a lipid-independent manner. The crystal structures of three Vγ4Vδ1 TCR-CD1a-lipid complexes reveal that the γδ TCR binds at the extreme far side and parallel to the long axis of the β-sheet floor of CD1a’s antigen-binding cleft. Here, the γδ TCR co-recognises the CD1a heavy chain and β2 microglobulin in a manner that is distinct from all other previously observed γδ 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 CD3ζ phosphorylation. In contrast with the ‘end to end’ binding of αβ TCRs that typically contact carried antigens, autoreactive γδ TCRs support geometrically diverse approaches to CD1a, as well as antigen independent recognition. 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 γδ T cell receptor.