Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, US.
Nat Commun. 2022 Jul 5;13(1):3872. doi: 10.1038/s41467-022-31443-9.
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.
CD1a 是树突状细胞上呈递脂质给 αβ T 细胞的单态抗原呈递分子。CD1a 是否代表其他免疫受体的配体仍不清楚。在这里，我们使用 CD1a 四聚体来表明 CD1a 是 Vδ1 γδ T 细胞的配体。功能研究表明，两种 γδ T 细胞受体 (TCR) 以脂质非依赖性方式结合 CD1a。三个 Vγ4Vδ1 TCR-CD1a-脂质复合物的晶体结构表明，γδ TCR 结合在 CD1a 抗原结合槽的 β 片层地板的极端远侧并与其平行。在这里，γδ TCR 以与所有其他先前观察到的 γδ TCR docking 模式不同的方式共同识别 CD1a 的重链和 β2 微球蛋白。自身反应性 CD1a 识别的“侧向”和非脂质抗原独立模式诱导 TCR 在细胞表面聚集，并通过 CD3ζ 磷酸化测量近端 T 细胞信号转导。与通常接触携带抗原的 αβ TCR 的“端到端”结合相反，自身反应性 γδ TCR 支持对 CD1a 的几何上多样化的方法，以及非抗原独立的识别。
