Structural Features of the αβTCR Mechanotransduction Apparatus That Promote pMHC Discrimination

The αβTCR was recently revealed to function as a mechanoreceptor. That is, it leverages mechanical energy generated during immune surveillance and at the immunological synapse to drive biochemical signaling following ligation by a specific foreign peptide–MHC complex (pMHC). Here, we review the structural features that optimize this transmembrane (TM) receptor for mechanotransduction. Specialized adaptations include (1) the CβFG loop region positioned between Vβ and Cβ domains that allosterically gates both dynamic T cell receptor (TCR)–pMHC bond formation and lifetime; (2) the rigid super β-sheet amalgams of heterodimeric CD3εγ and CD3εδ ectodomain components of the αβTCR complex; (3) the αβTCR subunit connecting peptides linking the extracellular and TM segments, particularly the oxidized CxxC motif in each CD3 heterodimeric subunit that facilitates force transfer through the TM segments and surrounding lipid, impacting cytoplasmic tail conformation; and (4) quaternary changes in the αβTCR complex that accompany pMHC ligation under load. How bioforces foster specific αβTCR-based pMHC discrimination and why dynamic bond formation is a primary basis for kinetic proofreading are discussed. We suggest that the details of the molecular rearrangements of individual αβTCR subunit components can be analyzed utilizing a combination of structural biology, single-molecule FRET, optical tweezers, and nanobiology, guided by insightful atomistic molecular dynamic studies. Finally, we review very recent data showing that the pre-TCR complex employs a similar mechanobiology to that of the αβTCR to interact with self-pMHC ligands, impacting early thymic repertoire selection prior to the CD4+CD8+ double positive thymocyte stage of development.

[1]  Gerhard Wagner,et al.  Force-dependent transition in the T-cell receptor β-subunit allosterically regulates peptide discrimination and pMHC bond lifetime , 2015, Proceedings of the National Academy of Sciences.

[2]  C. Murre,et al.  β-Selection-induced proliferation is required for αβ T cell differentiation. , 2012, Immunity.

[3]  J. Warwicker,et al.  The CXXC motif at the N terminus of an alpha-helical peptide. , 2006, Protein science : a publication of the Protein Society.

[4]  M. Cooper,et al.  The Evolution of Adaptive Immune Systems , 2006, Cell.

[5]  Robyn L Stanfield,et al.  How TCRs bind MHCs, peptides, and coreceptors. , 2006, Annual review of immunology.

[6]  S. Harrison,et al.  Crystal structure of a human CD3-epsilon/delta dimer in complex with a UCHT1 single-chain antibody fragment. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[7]  N. Manolios,et al.  The T cell antigen receptor α and β chains interact via distinct regions with CD3 chains , 1994 .

[8]  G. Crabtree,et al.  Signal transmission between the plasma membrane and nucleus of T lymphocytes. , 1994, Annual review of biochemistry.

[9]  E. Reinherz,et al.  Revisiting the putative TCR Cα dimerization model through structural analysis , 2013, Front. Immun..

[10]  E. Reinherz,et al.  Involvement of the TCR Cβ FG Loop in Thymic Selection and T Cell Function , 2002, The Journal of experimental medicine.

[11]  Mi-Hua Tao,et al.  Cutting Edge: Mechanical Forces Acting on T Cells Immobilized via the TCR Complex Can Trigger TCR Signaling , 2010, The Journal of Immunology.

[12]  C. Gouaillard,et al.  Evolution of T cell receptor (TCR) α β  heterodimer assembly with the CD3 complex , 2001 .

[13]  Hang Lu,et al.  Pre-TCR ligand binding impacts thymocyte development before αβTCR expression , 2015, Proceedings of the National Academy of Sciences.

[14]  Omer Dushek,et al.  Non‐catalytic tyrosine‐phosphorylated receptors , 2012, Immunological reviews.

[15]  K. Takase,et al.  [T cell activation]. , 1995, Ryumachi. [Rheumatism].

[16]  Ellis L. Reinherz,et al.  One of the CD3ε Subunits within a T Cell Receptor Complex Lies in Close Proximity to the Cβ FG Loop , 1998, The Journal of experimental medicine.

[17]  R. Germain,et al.  CD4+ T cell survival is not directly linked to self-MHC–induced TCR signaling , 2000, Nature Immunology.

[18]  T. Göbel,et al.  Evidence for a Stepwise Evolution of the CD3 Family1 , 2000, The Journal of Immunology.

[19]  K. P. Murphy,et al.  Janeway's immunobiology , 2007 .

[20]  E. Reinherz,et al.  Mechanisms Contributing to T Cell Receptor Signaling and Assembly Revealed by the Solution Structure of an Ectodomain Fragment of the CD3ϵγ Heterodimer , 2001, Cell.

[21]  T. Finkel,et al.  T cell receptor triggering by force. , 2010, Trends in immunology.

[22]  L. Pasquier,et al.  Biochemical analysis of the Xenopus laevis TCR/CD3 complex supports the "stepwise evolution" model , 2000, European journal of immunology.

[23]  E. Reinherz,et al.  A Conserved Hydrophobic Patch on Vβ Domains Revealed by TCRβ Chain Crystal Structures: Implications for Pre-TCR Dimerization , 2011, Front. Immun..

[24]  Lance C Kam,et al.  CD28 and CD3 have complementary roles in T-cell traction forces , 2014, Proceedings of the National Academy of Sciences.

[25]  A. Smolyar,et al.  Atomic structure of an αβ T cell receptor (TCR) heterodimer in complex with an anti‐TCR Fab fragment derived from a mitogenic antibody , 1998, The EMBO journal.

[26]  E. Reinherz,et al.  The TCR Cβ FG Loop Regulates αβ T Cell Development1 , 2006, The Journal of Immunology.

[27]  P. Marrack,et al.  A Conserved CXXC Motif in CD3ε Is Critical for T Cell Development and TCR Signaling , 2009, PLoS biology.

[28]  Oreste Acuto,et al.  Tailoring T-cell receptor signals by proximal negative feedback mechanisms , 2008, Nature Reviews Immunology.

[29]  E. Reinherz,et al.  Importance of the CD3γ Ectodomain Terminal β-Strand and Membrane Proximal Stalk in Thymic Development and Receptor Assembly1 , 2007, The Journal of Immunology.

[30]  K. Wucherpfennig,et al.  Stoichiometry of the T‐cell receptor–CD3 complex and key intermediates assembled in the endoplasmic reticulum , 2004, The EMBO journal.

[31]  Jia-huai Wang,et al.  The structural basis of αβ T‐lineage immune recognition: TCR docking topologies, mechanotransduction, and co‐receptor function , 2012, Immunological reviews.

[32]  Geoff P. O’Donoghue,et al.  Direct single molecule measurement of TCR triggering by agonist pMHC in living primary T cells , 2013, eLife.

[33]  Gerhard Wagner,et al.  Solution structure of the CD3εδ ectodomain and comparison with CD3εγ as a basis for modeling T cell receptor topology and signaling , 2004 .

[34]  K. Garcia,et al.  Molecular architecture of the αβ T cell receptor–CD3 complex , 2014, Proceedings of the National Academy of Sciences.

[35]  M. Crumpton,et al.  Molecular cloning of the cDNA encoding the T3 gamma subunit of the mouse T3/T cell antigen receptor complex. , 1987, Journal of immunology.

[36]  Amy M Becker,et al.  The Cytoplasmic Tail of the T Cell Receptor CD3 ε Subunit Contains a Phospholipid-Binding Motif that Regulates T Cell Functions1 , 2009, The Journal of Immunology.

[37]  M. Tokunaga,et al.  Mechanistic basis of pre–T cell receptor–mediated autonomous signaling critical for thymocyte development , 2006, Nature Immunology.

[38]  J. Warwicker,et al.  The CXXC motif at the N terminus of an α‐helical peptide , 2006 .

[39]  A. Ortiz,et al.  Cooperativity Between T Cell Receptor Complexes Revealed by Conformational Mutants of CD3ɛ , 2009, Science Signaling.

[40]  W. Hwang.  Calculation of conformation-dependent biomolecular forces. , 2007, The Journal of chemical physics.

[41]  J. Husson,et al.  Force Generation upon T Cell Receptor Engagement , 2011, PloS one.

[42]  P. Ricciardi-Castagnoli,et al.  Single-cell force spectroscopy: mechanical insights into the functional impacts of interactions between antigen-presenting cells and T cells , 2012, Immunologic research.

[43]  P. Bongrand,et al.  Force Measurements of TCR/pMHC Recognition at T Cell Surface , 2011, PloS one.

[44]  T. McKeithan,et al.  Kinetic proofreading in T-cell receptor signal transduction. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[45]  T. Beddoe,et al.  Crystal structure of the human T cell receptor CD3εγ heterodimer complexed to the therapeutic mAb OKT3 , 2004 .

[46]  P. T. Jones,et al.  Binding activities of a repertoire of single immunoglobulin variable domains secreted from Escherichia coli , 1989, Nature.

[47]  R. Varadarajan,et al.  Disulfide conformation and design at helix N‐termini , 2009, Proteins.

[48]  Arup K Chakraborty,et al.  Insights into the initiation of TCR signaling , 2014, Nature Immunology.

[49]  Omer Dushek,et al.  Basic residues in the T-cell receptor ζ cytoplasmic domain mediate membrane association and modulate signaling , 2011, Proceedings of the National Academy of Sciences.

[50]  J. Bonifacino,et al.  Pairwise, cooperative and inhibitory interactions describe the assembly and probable structure of the T‐cell antigen receptor. , 1991, The EMBO journal.

[51]  S. Harrison,et al.  Crystal structure of a human CD3-ε/δ dimer in complex with a UCHT1 single-chain antibody fragment , 2004 .

[52]  D. Discher,et al.  Mechanical Force in T Cell Receptor Signal Initiation , 2012, Front. Immun..

[53]  R. Aebersold,et al.  Constitutive tyrosine phosphorylation of the T-cell receptor (TCR) zeta subunit: regulation of TCR-associated protein tyrosine kinase activity by TCR zeta , 1993, Molecular and cellular biology.

[54]  L. K. Ely,et al.  Crystal structure of the human T cell receptor CD3 epsilon gamma heterodimer complexed to the therapeutic mAb OKT3. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[55]  张静,et al.  Banana Ovate family protein MaOFP1 and MADS-box protein MuMADS1 antagonistically regulated banana fruit ripening , 2015 .

[56]  Lode Wyns,et al.  Crystal structure of a camel single-domain VH antibody fragment in complex with lysozyme , 1996, Nature Structural Biology.

[57]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[58]  H. Boehmer.  The Thymus in Immunity and in Malignancy , 2014 .

[59]  V. Uversky,et al.  Lipid-binding activity of intrinsically unstructured cytoplasmic domains of multichain immune recognition receptor signaling subunits. , 2006, Biochemistry.

[60]  E. Eisenstein,et al.  Superantigen binding to a T cell receptor beta chain of known three- dimensional structure , 1995, The Journal of experimental medicine.

[61]  Gerhard Wagner,et al.  TCR Mechanobiology: Torques and Tunable Structures Linked to Early T Cell Signaling , 2012, Front. Immun..

[62]  M. Reth.  Antigen receptor tail clue , 1989, Nature.

[63]  J. Whisstock,et al.  A Structural Basis for the Selection of Dominant αβ T Cell Receptors in Antiviral Immunity , 2003 .

[64]  J. Kaufman,et al.  Structure of the Chicken CD3ϵδ/γ Heterodimer and Its Assembly with the αβT Cell Receptor* , 2014, The Journal of Biological Chemistry.

[65]  Alexander D. MacKerell,et al.  Improved treatment of the protein backbone in empirical force fields. , 2004, Journal of the American Chemical Society.

[66]  J. Coligan,et al.  The implications of subunit interactions for the structure of the T cell receptor‐CD3 complex , 1990, European journal of immunology.

[67]  E. Reinherz,et al.  The αβ T Cell Receptor Is an Anisotropic Mechanosensor* , 2009, The Journal of Biological Chemistry.

[68]  D. Keskin,et al.  Constitutively Oxidized CXXC Motifs within the CD3 Heterodimeric Ectodomains of the T Cell Receptor Complex Enforce the Conformation of Juxtaposed Segments* , 2014, The Journal of Biological Chemistry.

[69]  Etienne Gagnon,et al.  Regulation of T Cell Receptor Activation by Dynamic Membrane Binding of the CD3ɛ Cytoplasmic Tyrosine-Based Motif , 2008, Cell.

[70]  Jianpeng Ma,et al.  CHARMM: The biomolecular simulation program , 2009, J. Comput. Chem..

[71]  A. Weiss,et al.  ZAP-70 is constitutively associated with tyrosine-phosphorylated TCR zeta in murine thymocytes and lymph node T cells. , 1994, Immunity.

[72]  Howard T. Petrie,et al.  Mapping Precursor Movement through the Postnatal Thymus Reveals Specific Microenvironments Supporting Defined Stages of Early Lymphoid Development , 2001, The Journal of experimental medicine.

[73]  J. Strominger,et al.  Cross-linking of human T cell receptor proteins: association between the T cell idiotype β subunit and the T3 glycoprotein heavy subunit , 1985, Cell.

[74]  Mark M. Davis,et al.  TCR Signaling Emerges from the Sum of Many Parts , 2012, Front. Immun..

[75]  Martin Wiedmann,et al.  The Organizing Principle in the Formation of the T Cell Receptor-CD3 Complex , 2002, Cell.

[76]  E. Reinherz,et al.  Thymic selection is influenced by subtle structural variation involving the p4 residue of an MHC class I‐bound peptide , 2000, European journal of immunology.

[77]  N. K. Williams,et al.  The structural basis for autonomous dimerization of the pre-T-cell antigen receptor , 2010, Nature.

[78]  E. Reinherz,et al.  Distinctive CD3 Heterodimeric Ectodomain Topologies Maximize Antigen-Triggered Activation of αβ T Cell Receptors , 2010, The Journal of Immunology.

[79]  D. Aivazian,et al.  Phosphorylation of T cell receptor ζ is regulated by a lipid dependent folding transition , 2000, Nature Structural Biology.

[80]  R. Klausner,et al.  Activation of T cells by a tyrosine kinase activation domain in the cytoplasmic tail of CD3 epsilon. , 1992, Science.

[81]  Cheng Zhu,et al.  Accumulation of Dynamic Catch Bonds between TCR and Agonist Peptide-MHC Triggers T Cell Signaling , 2014, Cell.

[82]  James McCluskey,et al.  A structural basis for the selection of dominant alphabeta T cell receptors in antiviral immunity. , 2003, Immunity.

[83]  H. Eisen,et al.  Evidence that a single peptide-MHC complex on a target cell can elicit a cytolytic T cell response. , 1996, Immunity.