A correlation between TCR Valpha docking on MHC and CD8 dependence: implications for T cell selection.

T cell receptors (TCR) adopt a similar orientation when binding with major histocompatibility complex (MHC) molecules, yet the biological mechanism that generates this similar TCR orientation remains obscure. We show here the cocrystallographic structure of a mouse TCR bound to a human MHC molecule not seen by the TCR during thymic development. The orientation of this xenoreactive murine TCR atop human MHC deviates from the typical orientation more than any previously determined TCR/MHC structure. This unique orientation is solely due to the placement of the TCR Valpha domain on the MHC. In light of new information provided by this structure, we have reanalyzed the existing TCR/MHC cocrystal structures and discovered unique features of TCR Valpha domain position on class I MHC that correlate with CD8 dependence. Finally, we propose that the orientation seen in TCR recognition of MHC is a consequence of selection during T cell development.

[1]  David M. Kranz,et al.  TCRs with high affinity for foreign pMHC show self-reactivity , 2003, Nature Immunology.

[2]  J. Strominger,et al.  Superactivation of an immune response triggered by oligomerized T cell epitopes. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[3]  K. Sharp,et al.  Protein folding and association: Insights from the interfacial and thermodynamic properties of hydrocarbons , 1991, Proteins.

[4]  V. Engelhard,et al.  Isolation and characterization of monoclonal mouse cytotoxic T lymphocytes with specificity for HLA-A,B or -DR alloantigens. , 1982, Journal of immunology.

[5]  E. Reinherz,et al.  Expression, Purification, and Functional Analysis of Murine Ectodomain Fragments of CD8αα and CD8αβ Dimers* , 1999, The Journal of Biological Chemistry.

[6]  D. Littman,et al.  Disruption of T lymphocyte positive and negative selection in mice lacking the CD8 beta chain. , 1994, Immunity.

[7]  M. Bevan,et al.  CD8 lineage commitment in the absence of CD8. , 1997, Immunity.

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

[9]  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.

[10]  R. Henderson,et al.  Direct identification of an endogenous peptide recognized by multiple HLA-A2.1-specific cytotoxic T cells. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[11]  H. Ploegh Viral strategies of immune evasion. , 1998, Science.

[12]  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.

[13]  V S Lamzin,et al.  ARP/wARP and molecular replacement. , 2001, Acta crystallographica. Section D, Biological crystallography.

[14]  B. Baker,et al.  MHC Allele-Specific Molecular Features Determine Peptide/HLA-A2 Conformations That Are Recognized by HLA-A2-Restricted T Cell Receptors1 , 2002, The Journal of Immunology.

[15]  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.

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

[17]  L. Borysiewicz,et al.  Functional differences between influenza A-specific cytotoxic T lymphocyte clones expressing dominant and subdominant TCR. , 2001, International immunology.

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

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

[20]  S. Jameson,et al.  T-cell-receptor affinity and thymocyte positive selection , 1996, Nature.

[21]  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.

[22]  Z. Otwinowski,et al.  [20] Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

[23]  B K Jakobsen,et al.  T cell receptor and coreceptor CD8 alphaalpha bind peptide-MHC independently and with distinct kinetics. , 1999, Immunity.

[24]  F. Ramsdell,et al.  Engagement of CD4 and CD8 accessory molecules is required for T cell maturation. , 1989, Journal of immunology.

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

[26]  G. Gao,et al.  Antagonism of cytotoxic T-lymphocyte activation by soluble CD8 , 1999, Nature Medicine.

[27]  S. L. Silins,et al.  The immunology of Epstein-Barr virus infection. , 2001, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

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

[29]  Jorge Navaza,et al.  [33] AMoRe: An automated molecular replacement program package. , 1997, Methods in enzymology.

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

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

[32]  Mark M. Davis,et al.  T-cell antigen receptor genes and T-cell recognition , 1988, Nature.

[33]  P. Kavathas,et al.  Short related sequences in the cytoplasmic domains of CD4 and CD8 mediate binding to the amino-terminal domain of the p56lck tyrosine protein kinase , 1990, Molecular and cellular biology.

[34]  T. Mak,et al.  CD8 is needed for development of cytotoxic T but not helper T cells , 1991, Cell.

[35]  S. Rowland-Jones,et al.  Persistent high frequency of human immunodeficiency virus-specific cytotoxic T cells in peripheral blood of infected donors. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[36]  R. Germain T-cell development and the CD4–CD8 lineage decision , 2002, Nature Reviews Immunology.

[37]  D. Covell,et al.  Differential contact of disparate class I/peptide complexes as the basis for epitope cross-recognition by a single T cell receptor. , 1997, Journal of immunology.

[38]  P. A. Peterson,et al.  CD8 enhances formation of stable T-cell receptor/MHC class I molecule complexes , 1996, Nature.

[39]  Annette Oxenius,et al.  Formation of TCR dimers/trimers as a crucial step for T cell activation , 1998, European journal of immunology.

[40]  R. Read,et al.  Improved Structure Refinement Through Maximum Likelihood , 1996 .

[41]  E. Appella,et al.  Structural Evidence of  T Cell Xeno-reactivity in the Absence of Molecular Mimicry , 1999, The Journal of experimental medicine.

[42]  E J Dodson,et al.  Collaborative Computational Project, number 4: providing programs for protein crystallography. , 1997, Methods in enzymology.

[43]  T. Mak,et al.  Reduced thymic maturation but normal effector function of CD8+ T cells in CD8 beta gene-targeted mice , 1994, The Journal of experimental medicine.

[44]  S. Jameson,et al.  Critical Role for Cd8 in T Cell Receptor Binding and Activation by Peptide/Major Histocompatibility Complex Multimers , 2000, The Journal of experimental medicine.

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

[46]  D. Stuart,et al.  Crystal structure of the complex between human CD8αα and HLA-A2 , 1997, Nature.

[47]  R. Perlmutter,et al.  Interaction of the unique N-terminal region of tyrosine kinase p56 lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs , 1990, Cell.

[48]  M. Bachmann,et al.  Selection of the T cell repertoire. , 1999, Annual review of immunology.

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

[50]  Edward J. Collins,et al.  High Affinity Xenoreactive TCR:MHC Interaction Recruits CD8 in Absence of Binding to MHC1 , 2003, The Journal of Immunology.

[51]  M. Lawrence,et al.  Shape complementarity at protein/protein interfaces. , 1993, Journal of molecular biology.

[52]  E. Palmer,et al.  Essential Role of CD8 Palmitoylation in CD8 Coreceptor Function1 , 2000, The Journal of Immunology.

[53]  Mike Carson,et al.  Ribbon models of macromolecules , 1987 .

[54]  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.

[55]  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.

[56]  A. Smolyar,et al.  Structural Basis of CD8 Coreceptor Function Revealed by Crystallographic Analysis of a Murine CD8αα Ectodomain Fragment in Complex with H-2Kb , 1998 .

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

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

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

[60]  D. Wiley,et al.  HLA-A2-peptide complexes: refolding and crystallization of molecules expressed in Escherichia coli and complexed with single antigenic peptides. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[61]  H. Lodish,et al.  Zinc Is Essential for Binding of p56 lck to CD4 and CD8α* , 1998, The Journal of Biological Chemistry.

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

[63]  J. Altman,et al.  CD8 binding to MHC class I molecules is influenced by T cell maturation and glycosylation. , 2001, Immunity.

[64]  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.

[65]  L. Sherman,et al.  Selecting T cell receptors with high affinity for self-MHC by decreasing the contribution of CD8. , 1992, Science.

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

[67]  K. Garcia,et al.  Alanine Scanning Mutagenesis of an αβ T Cell Receptor: Mapping the Energy of Antigen Recognition , 1998 .

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

[69]  E. Reinherz,et al.  Developmentally Regulated Glycosylation of the CD8αβ Coreceptor Stalk Modulates Ligand Binding , 2001, Cell.