What do TCR-pMHC crystal structures teach us about MHC restriction and alloreactivity?

Abstract MHC-encoded molecules govern immune responses by presenting antigenic peptides to T-cell receptors (TCRs). Several crystal structures of TCR–pMHC (peptide–MHC) complexes have unveiled the atomic details of this interaction, which is crucial to T-cell activation. By combining these data with biological and thermodynamical results, we revisit the structural basis of TCR crossreactivity and alloreactivity and the dynamics of the TCR binding process. Some emerging principles are at variance with recently proposed models of TCR recognition that would bring one back to ‘dual recognition' models, in which TCR discriminates which part of its ligand is MHC and which part is peptide.

[1]  P. Rohrlich,et al.  Comparative analysis of the CD8(+) T cell repertoires of H-2 class I wild-type/HLA-A2.1 and H-2 class I knockout/HLA-A2.1 transgenic mice. , 2002, International immunology.

[2]  Michelle R. Arkin,et al.  Binding of small molecules to an adaptive protein–protein interface , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Bernard Malissen,et al.  An evolutionary and structural perspective on T cell antigen receptor function , 2003, Immunological reviews.

[4]  M. Bevan,et al.  Hypothesis: why do so many lymphocytes respond to major histocompatibility antigens? , 1977, Cellular immunology.

[5]  T. Ohta,et al.  Population Biology of Antigen Presentation by MHC Class I Molecules , 1996, Science.

[6]  B. Braden,et al.  Crystal Structure of the Vα Domain of a T Cell Antigen Receptor , 1995, Science.

[7]  R. Germain,et al.  Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes , 2002, Nature.

[8]  Bernard Malissen,et al.  Crystal structure of a T cell receptor bound to an allogeneic MHC molecule , 2000, Nature Immunology.

[9]  E A Merritt,et al.  Raster3D: photorealistic molecular graphics. , 1997, Methods in enzymology.

[10]  Don C. Wiley,et al.  Structure of a Complex of the Human α/β T Cell Receptor (TCR) HA1.7, Influenza Hemagglutinin Peptide, and Major Histocompatibility Complex Class II Molecule, HLA-DR4 (DRA0101 and DRB10401) , 2002, The Journal of experimental medicine.

[11]  K. Garcia,et al.  A functional hot spot for antigen recognition in a superagonist TCR/MHC complex. , 2000, Immunity.

[12]  Ian A Wilson,et al.  Structural and thermodynamic correlates of T cell signaling. , 2002, Annual review of biophysics and biomolecular structure.

[13]  J. Zerrahn,et al.  The MHC Reactivity of the T Cell Repertoire Prior to Positive and Negative Selection , 1997, Cell.

[14]  Z Reich,et al.  Thermodynamics of T cell receptor binding to peptide-MHC: evidence for a general mechanism of molecular scanning. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[15]  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.

[16]  R. Mariuzza,et al.  Crystal structure of the beta chain of a T cell antigen receptor. , 1995, Science.

[17]  M. Cohn.  Tritope model of restrictive recognition by the TCR. , 2003, Trends in immunology.

[18]  Jia-huai Wang,et al.  Structural basis of T cell recognition of peptides bound to MHC molecules. , 2002, Molecular immunology.

[19]  A. Fersht,et al.  Structure of the transition state for folding of a protein derived from experiment and simulation. , 1996, Journal of molecular biology.

[20]  H. Rammensee,et al.  The Role of Peptides in T Cell Alloreactivity Is Determined by Self–Major Histocompatibility Complex Molecules , 2000, The Journal of experimental medicine.

[21]  D. Mason,et al.  A very high level of crossreactivity is an essential feature of the T-cell receptor. , 1998, Immunology today.

[22]  H. Macdonald,et al.  Cytolytic T lymphocyte precursors reactive against mutant Kb alloantigens are as frequent as those reactive against a whole foreign haplotype. , 1980, Journal of immunology.

[23]  P. Anton van der Merwe,et al.  CDR3 loop flexibility contributes to the degeneracy of TCR recognition , 2003, Nature Immunology.

[24]  Arne Svejgaard,et al.  A functional and structural basis for TCR cross-reactivity in multiple sclerosis , 2002, Nature Immunology.

[25]  D. Wiley,et al.  Two human T cell receptors bind in a similar diagonal mode to the HLA-A2/Tax peptide complex using different TCR amino acids. , 1998, Immunity.

[26]  A. Fersht,et al.  Characterizing transition states in protein folding: an essential step in the puzzle. , 1995, Current opinion in structural biology.

[27]  L R Pease,et al.  Structural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen. , 1998, Science.

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

[29]  B M Baker,et al.  Four A6-TCR/peptide/HLA-A2 structures that generate very different T cell signals are nearly identical. , 1999, Immunity.

[30]  P. Marrack,et al.  Major histocompatibility complex proteins and TCRs: do they really go together like a horse and carriage? , 2001, Journal of immunology.

[31]  Vasso Apostolopoulos,et al.  Structural Comparison of Allogeneic and Syngeneic T Cell Receptor–Peptide-Major Histocompatibility Complex Complexes , 2002, The Journal of experimental medicine.

[32]  Cyrus Chothia,et al.  Canonical structures for the hypervariable regions of T cell αβ receptors 1 1 Edited by J. M. Thornton , 2000 .

[33]  E. Goldman,et al.  A mutational analysis of binding interactions in an antigen-antibody protein-protein complex. , 1998, Biochemistry.

[34]  Bernard Malissen,et al.  A T cell receptor CDR3beta loop undergoes conformational changes of unprecedented magnitude upon binding to a peptide/MHC class I complex. , 2002, Immunity.

[35]  T. Schumacher,et al.  Are MHC-bound peptides a nuisance for positive selection? , 1994, Immunity.

[36]  T. Fujisawa,et al.  Predominant Role of T Cell Receptor (TCR)-α Chain in Forming Preimmune TCR Repertoire Revealed by Clonal TCR Reconstitution System , 2002, The Journal of experimental medicine.

[37]  R. Zinkernagel,et al.  Specificity of Virus‐Immune Effector T Cells for H‐2K or H‐2D Compatible Interactions: Implications for H‐Antigen Diversity , 1976, Transplantation reviews.

[38]  Partho Ghosh,et al.  Structure of the complex between human T-cell receptor, viral peptide and HLA-A2 , 1996, Nature.

[39]  J. Forman,et al.  Use ofH-2 mutations to quantitate alloreactivity: Alloreactivity is strongest against H-2 antigens which are closest to self , 2005, Immunogenetics.

[40]  Dan S. Tawfik,et al.  Antibody Multispecificity Mediated by Conformational Diversity , 2003, Science.

[41]  Mark M. Davis,et al.  Two-step binding mechanism for T-cell receptor recognition of peptide–MHC , 2002, Nature.

[42]  P. Kraulis.  A program to produce both detailed and schematic plots of protein structures , 1991 .

[43]  D. Fremont,et al.  Structural Basis of Cytochrome c Presentation by IEk , 2002, The Journal of experimental medicine.

[44]  A. Smolyar,et al.  The crystal structure of a T cell receptor in complex with peptide and MHC class II. , 1999, Science.

[45]  C. Benoist,et al.  The shaping of the T cell repertoire. , 2001, Immunity.

[46]  W. Delano.  Unraveling hot spots in binding interfaces: progress and challenges. , 2002, Current opinion in structural biology.

[47]  Ian A Wilson,et al.  The specificity of TCR/pMHC interaction. , 2002, Current opinion in immunology.

[48]  P. A. Peterson,et al.  Crystal structure of mouse CD1: An MHC-like fold with a large hydrophobic binding groove. , 1997, Science.

[49]  Iannis Aifantis,et al.  Thymic selection revisited: how essential is it? , 2003, Immunological reviews.

[50]  Robyn L. Stanfield,et al.  An αβ T Cell Receptor Structure at 2.5 Å and Its Orientation in the TCR-MHC Complex , 1996, Science.

[51]  S. Jameson,et al.  Role of 2c T Cell Receptor Residues in the Binding of Self–And Allo–Major Histocompatibility Complexes , 2000, The Journal of experimental medicine.

[52]  M. Bevan,et al.  High determinant density may explain the phenomenon of alloreactivity. , 1984, Immunology today.

[53]  P. A. Peterson,et al.  Structural basis of 2C TCR allorecognition of H-2Ld peptide complexes. , 1998, Immunity.

[54]  Gerhard Wagner,et al.  Structure, specificity and CDR mobility of a class II restricted single-chain T-cell receptor , 1999, Nature Structural Biology.

[55]  D. Wiley,et al.  Structure of a covalently stabilized complex of a human αβ T‐cell receptor, influenza HA peptide and MHC class II molecule, HLA‐DR1 , 2000, The EMBO journal.

[56]  Olivier Lantz,et al.  Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1 , 2003, Nature.

[57]  K. Garcia,et al.  Not just any T cell receptor will do. , 2003, Immunity.

[58]  J. Fontecilla-Camps,et al.  The three‐dimensional structure of a T‐cell antigen receptor VαVβ heterodimer reveals a novel arrangement of the Vβ domain , 1997 .

[59]  B K Jakobsen,et al.  TCR binding to peptide-MHC stabilizes a flexible recognition interface. , 1999, Immunity.

[60]  J. Shabanowitz,et al.  Identification of endogenous peptides recognized by in vivo or in vitro generated alloreactive cytotoxic T lymphocytes: distinct characteristics correlated with CD8 dependence , 2001, European journal of immunology.

[61]  Brian M. Baker,et al.  Identification of a Crucial Energetic Footprint on the α1 Helix of Human Histocompatibility Leukocyte Antigen (Hla)-A2 That Provides Functional Interactions for Recognition by Tax Peptide/Hla-A2–Specific T Cell Receptors , 2001, The Journal of experimental medicine.