T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I–bound peptide

Unusually long major histocompatibility complex (MHC) class I–restricted epitopes are important in immunity, but their 'bulged' conformation represents a potential obstacle to αβ T cell receptor (TCR)–MHC class I docking. To elucidate how such recognition is achieved while still preserving MHC restriction, we have determined here the structure of a TCR in complex with HLA-B*3508 presenting a peptide 13 amino acids in length. This complex was atypical of TCR–peptide–MHC class I interactions, being dominated at the interface by peptide-mediated interactions. The TCR assumed two distinct orientations, swiveling on top of the centrally bulged, rigid peptide such that only limited contacts were made with MHC class I. Although the TCR-peptide recognition resembled an antibody-antigen interaction, the TCR–MHC class I contacts defined a minimal 'generic footprint' of MHC-restriction. Thus our findings simultaneously demonstrate the considerable adaptability of the TCR and the 'shape' of MHC restriction.

[1]  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.

[2]  R. Kridel,et al.  An Alternative Open Reading Frame of the Human Macrophage Colony-Stimulating Factor Gene Is Independently Translated and Codes for an Antigenic Peptide of 14 Amino Acids Recognized by Tumor-Infiltrating Cd8 T Lymphocytes , 2001, The Journal of experimental medicine.

[3]  William S. Lane,et al.  Different length peptides bind to HLA-Aw68 similarly at their ends but bulge out in the middle , 1992, Nature.

[4]  Marie-Paule Lefranc,et al.  IMGT, the international ImMunoGeneTics database , 1999, Nucleic Acids Res..

[5]  G W Butcher,et al.  Two different, highly exposed, bulged structures for an unusually long peptide bound to rat MHC class I RT1-Aa. , 2001, Immunity.

[6]  A Sette,et al.  Naturally processed peptides longer than nine amino acid residues bind to the class I MHC molecule HLA-A2.1 with high affinity and in different conformations. , 1994, Journal of immunology.

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

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

[9]  P. A. Peterson,et al.  Crystal structures of two viral peptides in complex with murine MHC class I H-2Kb. , 1994, Science.

[10]  J. Wells,et al.  A systematic mutational analysis of hormone-binding determinants in the human growth hormone receptor. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[11]  M. Probst-Kepper,et al.  Conformational Restraints and Flexibility of 14-Meric Peptides in Complex with HLA-B*35011 , 2004, The Journal of Immunology.

[12]  L. K. Ely,et al.  The CDR3 regions of an immunodominant T cell receptor dictate the 'energetic landscape' of peptide-MHC recognition , 2005, Nature Immunology.

[13]  William Arbuthnot Sir Lane,et al.  A subset of HLA-B27 molecules contains peptides much longer than nonamers. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[14]  A. Goldberg,et al.  The importance of the proteasome and subsequent proteolytic steps in the generation of antigenic peptides. , 2002, Molecular immunology.

[15]  P. Cresswell,et al.  Impaired assembly and transport of HLA‐A and ‐B antigens in a mutant TxB cell hybrid. , 1986, The EMBO journal.

[16]  J A Wells,et al.  Dissecting the energetics of an antibody‐antigen interface by alanine shaving and molecular grafting , 1994, Protein science : a publication of the Protein Society.

[17]  G. Cohen,et al.  Interactions of protein antigens with antibodies. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[18]  N. Papadopoulos,et al.  Binding of longer peptides to the H-2Kb heterodimer is restricted to peptides extended at their C terminus: refinement of the inherent MHC class I peptide binding criteria. , 1999, Journal of immunology.

[19]  G. Thomas,et al.  Bi-cycling the furin pathway: from TGN localization to pathogen activation and embryogenesis. , 1999, Trends in cell biology.

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

[21]  M. Bonneville,et al.  Gamma delta T cells. , 1990 .

[22]  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.

[23]  J. Neefjes,et al.  Peptide selection by MHC-encoded TAP transporters. , 1994, Current opinion in immunology.

[24]  Mark M Davis,et al.  T cell killing does not require the formation of a stable mature immunological synapse , 2004, Nature Immunology.

[25]  D. Blaas,et al.  Crystal structure of a human rhinovirus neutralizing antibody complexed with a peptide derived from viral capsid protein VP2. , 1994, The EMBO journal.

[26]  J. Sacchettini,et al.  Crystal structure of the major histocompatibility complex class I H-2Kb molecule containing a single viral peptide: implications for peptide binding and T-cell receptor recognition. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

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

[28]  D. Garboczi,et al.  Shapes of MHC restriction. , 1999, Immunity.

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

[30]  J. Claverie,et al.  The peptidic self model: a reassessment of the role of the major histocompatibility complex molecules in the restriction of the T-cell response. , 1986, Annales de l'Institut Pasteur. Immunology.

[31]  Mark M Davis,et al.  How T cells 'see' antigen , 2005, Nature Immunology.

[32]  K. Garcia,et al.  Structural basis of T cell recognition. , 1999, Annual review of immunology.

[33]  G. Murshudov,et al.  Refinement of macromolecular structures by the maximum-likelihood method. , 1997, Acta crystallographica. Section D, Biological crystallography.

[34]  Simon J Davis,et al.  Molecular interactions mediating T cell antigen recognition. , 2003, Annual review of immunology.

[35]  H. Rammensee,et al.  Peptides naturally presented by MHC class I molecules. , 1993, Annual review of immunology.

[36]  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.

[37]  Z. Otwinowski,et al.  Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

[38]  A. Goldberg,et al.  The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8–9 residues , 2002, Nature Immunology.

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

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

[41]  S. L. Silins,et al.  T cell receptor repertoire for a viral epitope in humans is diversified by tolerance to a background major histocompatibility complex antigen , 1995, The Journal of experimental medicine.

[42]  D. Wiley,et al.  The antigenic identity of peptide-MHC complexes: A comparison of the conformations of five viral peptides presented by HLA-A2 , 1993, Cell.

[43]  J. A. Payne,et al.  Differential transport requirements of HLA and H-2 class I glycoproteins , 2004, Immunogenetics.

[44]  Wendy J M van Zuylen,et al.  Potent T cell response to a class I‐binding 13‐mer viral epitope and the influence of HLA micropolymorphism in controlling epitope length , 2004, European journal of immunology.

[45]  F. Ginhoux,et al.  Quantifying Recruitment of Cytosolic Peptides for HLA Class I Presentation: Impact of TAP Transport1 , 2003, The Journal of Immunology.

[46]  G N Murshudov,et al.  Use of TLS parameters to model anisotropic displacements in macromolecular refinement. , 2001, Acta crystallographica. Section D, Biological crystallography.

[47]  David I Stuart,et al.  A structural basis for immunodominant human T cell receptor recognition , 2003, Nature Immunology.

[48]  James McCluskey,et al.  A Naturally Selected Dimorphism within the HLA-B44 Supertype Alters Class I Structure, Peptide Repertoire, and T Cell Recognition , 2003, The Journal of experimental medicine.

[49]  K. Wucherpfennig,et al.  Unconventional topology of self peptide–major histocompatibility complex binding by a human autoimmune T cell receptor , 2005, Nature Immunology.

[50]  Randy J Read,et al.  Electronic Reprint Biological Crystallography Likelihood-enhanced Fast Rotation Functions Biological Crystallography Likelihood-enhanced Fast Rotation Functions , 2003 .

[51]  J. Beck,et al.  Strategic Mutations in the Class I Major Histocompatibility Complex HLA-A2 Independently Affect Both Peptide Binding and T Cell Receptor Recognition* , 2004, Journal of Biological Chemistry.

[52]  Natalie A Borg,et al.  High Resolution Structures of Highly Bulged Viral Epitopes Bound to Major Histocompatibility Complex Class I , 2005, Journal of Biological Chemistry.

[53]  A. Townsend,et al.  Antigen recognition by class I-restricted T lymphocytes. , 1989, Annual review of immunology.

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

[55]  Morgan Huse,et al.  Agonist/endogenous peptide–MHC heterodimers drive T cell activation and sensitivity , 2005, Nature.

[56]  K. Christopher Garcia,et al.  Structure of a γδ T Cell Receptor in Complex with the Nonclassical MHC T22 , 2005, Science.

[57]  Mark M Davis,et al.  Evidence that structural rearrangements and/or flexibility during TCR binding can contribute to T cell activation. , 2003, Molecular cell.

[58]  J. McCluskey,et al.  Identification of a dominant self‐ligand bound to three HLA B44 alleles and the preliminary crystallographic analysis of recombinant forms of each complex , 2002, FEBS letters.

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

[60]  Philip J Norris,et al.  A hairpin turn in a class II MHC-bound peptide orients residues outside the binding groove for T cell recognition. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[61]  N. Shastri,et al.  ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum , 2002, Nature.

[62]  D. Lo,et al.  Preferential expression of TCR V alpha regions in CD4/CD8 subsets: class discrimination or co-receptor recognition? , 1998, Immunology today.

[63]  D. Wiley,et al.  The three-dimensional structure of a class I major histocompatibility complex molecule missing the alpha 3 domain of the heavy chain. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[64]  R. Zinkernagel,et al.  Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system , 1974, Nature.

[65]  J. McCluskey,et al.  The production, purification and crystallization of a soluble heterodimeric form of a highly selected T-cell receptor in its unliganded and liganded state. , 2002, Acta crystallographica. Section D, Biological crystallography.

[66]  J. Zou,et al.  Improved methods for building protein models in electron density maps and the location of errors in these models. , 1991, Acta crystallographica. Section A, Foundations of crystallography.

[67]  Mark M. Davis,et al.  Direct observation of ligand recognition by T cells , 2002, Nature.

[68]  D. Hafler,et al.  Conserved CDR3 Regions in T-Cell Receptor (TCR) CD8+T Cells That Recognize the Tax11-19/HLA-A*0201 Complex in a Subject Infected with Human T-Cell Leukemia Virus Type 1: Relationship of T-Cell Fine Specificity and Major Histocompatibility Complex/Peptide/TCR Crystal Structure , 2001, Journal of Virology.