title: Pre-T Cell Receptors (Pre-TCRs) Leverage Vβ Complementarity Determining Regions (CDRs) and Hydrophobic Patch in Mechanosensing Thymic Self-ligands.
abstract: The pre-T cell receptor (pre-TCR) is a pTα-β heterodimer functioning in early αβ T cell development. Although once thought to be ligand-autonomous, recent studies show that pre-TCRs participate in thymic repertoire formation through recognition of peptides bound to major histocompatibility molecules (pMHC). Using optical tweezers, we probe pre-TCR bonding with pMHC at the single molecule level. Like the αβTCR, the pre-TCR is a mechanosensor undergoing force-based structural transitions that dynamically enhance bond lifetimes and exploiting allosteric control regulated via the Cβ FG loop region. The pre-TCR structural transitions exhibit greater reversibility than TCRαβ and ordered force-bond lifetime curves. Higher piconewton force requires binding through both complementarity determining region loops and hydrophobic Vβ patch apposition. This patch functions in the pre-TCR as a surrogate Vα domain, fostering ligand promiscuity to favor development of β chains with self-reactivity but is occluded by α subunit replacement of pTα upon αβTCR formation. At the double negative 3 thymocyte stage where the pre-TCR is first expressed, pre-TCR interaction with self-pMHC ligands imparts growth and survival advantages as revealed in thymic stromal cultures, imprinting fundamental self-reactivity in the T cell repertoire. Collectively, our data imply the existence of sequential mechanosensor αβTCR repertoire tuning via the pre-TCR.
authors.affiliation: From the Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: Dibyendu Kumar
authors.initials: DK
authors.lastname: Das
authors.affiliation: the Departments of Biological Chemistry and Molecular Pharmacology and.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mallis
authors.affiliation: the Department of Medical Oncology, Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, and.|Medicine, Harvard Medical School, and.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Duke-Cohan
authors.affiliation: the Department of Medical Oncology, Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, and.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Hussey
authors.affiliation: the Department of Medical Oncology, Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, and.|Medicine, Harvard Medical School, and.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Tetteh
authors.affiliation: From the Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: Mark
authors.initials: M
authors.lastname: Hilton
authors.affiliation: the Departments of Biological Chemistry and Molecular Pharmacology and.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
authors.affiliation: From the Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37235, matt.lang@vanderbilt.edu.|the Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37235.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Lang
authors.affiliation: the Department of Medical Oncology, Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, and ellis_reinherz@dfci.harvard.edu.|Medicine, Harvard Medical School, and.
authors.forename: Ellis L
authors.initials: EL
authors.lastname: Reinherz
mesh_terms: D000818:Animals; D022801:Complementarity Determining Regions / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D017433:Protein Structure, Secondary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D060168:Thymocytes / Q000737:chemistry / Q000166:cytology / Q000378:metabolism
chemical_list: D022801:Complementarity Determining Regions; D016693:Receptors, Antigen, T-Cell, alpha-beta
keywords: allosteric regulation; cell differentiation; cell surface receptor; crystallography; major histocompatibility complex (MHC); mechanobiology; nuclear magnetic resonance (NMR); optical tweezers; pre-T cell receptor; structural transition