FCCC LOGO Faculty Publications
Kim ST , Touma M , Takeuchi K , Sun ZYJ , Dave VP , Kappes DJ , Wagner G , Reinherz EL
Distinctive CD3 Heterodimeric Ectodomain Topologies Maximize Antigen-Triggered Activation of alpha beta T Cell Receptors
Journal of Immunology. 2010 Sep;185(5) :2951-2959
PMCID: PMC2936104   
Back to previous list
The alpha beta TCR has recently been suggested to function as an anisotropic mechanosensor during immune surveillance, converting mechanical energy into a biochemical signal upon specific peptide/MHC ligation of the alpha beta clonotype. The heterodimeric CD3 epsilon gamma and CD3 epsilon delta subunits, each composed of two Ig-like ectodomains, form unique side-to-side hydrophobic interfaces involving their paired G-strands, rigid connectors to their respective transmembrane segments. Those dimers are laterally disposed relative to the alpha beta heterodimer within the TCR complex. In this paper, using structure-guided mutational analysis, we investigate the functional consequences of a striking asymmetry in CD3 gamma and CD3 delta G-strand geometries impacting ectodomain shape. The uniquely kinked conformation of the CD3 gamma G-strand is crucial for maximizing Ag-triggered TCR activation and surface TCR assembly/expression, offering a geometry to accommodate juxtaposition of CD3 gamma and TCR beta ectodomains and foster quaternary change that cannot be replaced by the isologous CD3 delta subunit's extracellular region. TCR beta and CD3 subunit protein sequence analyses among Gnathostomata species show that the C beta FG loop and CD3 gamma subunit coevolved, consistent with this notion. Furthermore, restoration of T cell activation and development in CD3 gamma(-/-) mouse T lineage cells by interspecies replacement can be rationalized from structural insights on the topology of chimeric mouse/human CD3 epsilon delta dimers. Most importantly, our findings imply that CD3 gamma and CD3 delta evolved from a common precursor gene to optimize peptide/MHC-triggered alpha beta TCR activation. The Journal of Immunology, 2010, 185: 2951-2959.
Kim, Sun Taek Touma, Maki Takeuchi, Koh Sun, Zhen-Yu J. Dave, Vibhuti P. Kappes, Dietmar J. Wagner, Gerhard Reinherz, Ellis L. Amer assoc immunologists Bethesda 641jx