title: Distinctive CD3 heterodimeric ectodomain topologies maximize antigen-triggered activation of alpha beta T cell receptors.
abstract: The alphabeta 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 alphabeta clonotype. The heterodimeric CD3epsilongamma and CD3epsilondelta 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 alphabeta heterodimer within the TCR complex. In this paper, using structure-guided mutational analysis, we investigate the functional consequences of a striking asymmetry in CD3gamma and CD3delta G-strand geometries impacting ectodomain shape. The uniquely kinked conformation of the CD3gamma G-strand is crucial for maximizing Ag-triggered TCR activation and surface TCR assembly/expression, offering a geometry to accommodate juxtaposition of CD3gamma and TCR beta ectodomains and foster quaternary change that cannot be replaced by the isologous CD3delta subunit's extracellular region. TCRbeta and CD3 subunit protein sequence analyses among Gnathostomata species show that the Cbeta FG loop and CD3gamma subunit coevolved, consistent with this notion. Furthermore, restoration of T cell activation and development in CD3gamma(-/-) mouse T lineage cells by interspecies replacement can be rationalized from structural insights on the topology of chimeric mouse/human CD3epsilondelta dimers. Most importantly, our findings imply that CD3gamma and CD3delta evolved from a common precursor gene to optimize peptide/MHC-triggered alphabeta TCR activation.
authors.affiliation: Laboratory of Immunobiology and Department of Medical Oncology, Dana-Farber Cancer Institute, MA 02115, USA.
authors.forename: Sun Taek
authors.initials: ST
authors.lastname: Kim
authors.forename: Maki
authors.initials: M
authors.lastname: Touma
authors.forename: Koh
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Zhen-Yu J
authors.initials: ZY
authors.lastname: Sun
authors.forename: Vibhuti P
authors.initials: VP
authors.lastname: Dave
authors.forename: Dietmar J
authors.initials: DJ
authors.lastname: Kappes
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
authors.forename: Ellis L
authors.initials: EL
authors.lastname: Reinherz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017252:CD3 Complex / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D019143:Evolution, Molecular; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009924:Organ Culture Techniques; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism* / Q000502:physiology; D012756:Sheep; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D017252:CD3 Complex; C452842:CD3 antigen, gamma chain; C472562:CD3delta antigen; C485468:Cd3e protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta