Molecular basis for the recognition of two structurally different major histocompatibility complex/peptide complexes by a single T-cell receptor.

2C is a typical alloreactive cytotoxic T lymphocyte clone that recognizes two different ligands. These ligands are adducts of the allo-major histocompatibility complex (MHC) molecule H-2Ld and an endogenous octapeptide, and of the self-MHC molecule H-2Kb and another peptide. MHC-binding and T-cell assays with synthetic peptides in combination with molecular modeling studies were employed to analyze the structural basis for this crossreactivity. The molecular surfaces of the two complexes differ greatly in densities and distributions of positive and negative charges. However, modifications of the peptides that increase similarity decrease the capacities of the resulting MHC peptide complexes to induce T-cell responses. Moreover, the roles of the peptides in ligand recognition are different for self- and allo-MHC-restricted T-cell responses. The self-MHC-restricted T-cell responses were finely tuned to recognition of the peptide. The allo-MHC-restricted responses, on the other hand, largely ignore modifications of the peptide. The results strongly suggest that adaptation of the T-cell receptor to the different ligand structures, rather than molecular mimicry by the ligands, is the basis for the crossreactivity of 2C. This conclusion has important implications for T-cell immunology and for the understanding of immunological disorders.

[1]  P. A. Peterson,et al.  Crystal structure of an H-2Kb-ovalbumin peptide complex reveals the interplay of primary and secondary anchor positions in the major histocompatibility complex binding groove. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[2]  M. Bevan,et al.  Positive selection of CD8+ T cells induced by major histocompatibility complex binding peptides in fetal thymic organ culture , 1993, The Journal of experimental medicine.

[3]  D. Osguthorpe,et al.  Structure and energetics of ligand binding to proteins: Escherichia coli dihydrofolate reductase‐trimethoprim, a drug‐receptor system , 1988, Proteins.

[4]  L. Hood,et al.  DNA sequence of a gene encoding a BALB/c mouse Ld transplantation antigen. , 1982, Science.

[5]  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.

[6]  P. Marrack,et al.  The Repertoire of T Cells Shaped by a Single MHC/Peptide Ligand , 1996, Cell.

[7]  S. Wilson,et al.  Applications of simulated annealing to peptides , 1990, Biopolymers.

[8]  S. Tonegawa,et al.  Peptide contributes to the specificity of positive selection of CD8+ T cells in the thymus , 1993, Cell.

[9]  D Rognan,et al.  Molecular dynamics study of a complex between the human histocompatibility antigen HLA-A2 and the IMP58-66 nonapeptide from influenza virus matrix protein. , 1992, European journal of biochemistry.

[10]  M. Jackson,et al.  High-affinity reactions between antigen-specific T-cell receptors and peptides associated with allogeneic and syngeneic major histocompatibility complex class I proteins. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[11]  S. Kienle,et al.  Decrypting the structure of major histocompatibility complex class I- restricted cytotoxic T lymphocyte epitopes with complex peptide libraries , 1995, The Journal of experimental medicine.

[12]  W. Lie,et al.  Peptide ligand-induced conformation and surface expression of the Ld class I MHC molecule , 1990, Nature.

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

[14]  J. Strominger,et al.  Molecular mimicry in T cell-mediated autoimmunity: Viral peptides activate human T cell clones specific for myelin basic protein , 1995, Cell.

[15]  S. Kienle,et al.  Self-MHC-restricted peptides recognized by an alloreactive T lymphocyte clone. , 1996, Journal of immunology.

[16]  M. Ultsch,et al.  Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. , 1992, Science.

[17]  H. Ljunggren,et al.  Host resistance directed selectively against H-2-deficient lymphoma variants. Analysis of the mechanism , 1985, The Journal of experimental medicine.

[18]  D. Sherman,et al.  Immunoprecipitation of cell surface structures of cloned cytotoxic T lymphocytes by clone-specific antisera. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[19]  D. E. Anderson,et al.  pH-induced denaturation of proteins: a single salt bridge contributes 3-5 kcal/mol to the free energy of folding of T4 lysozyme. , 1990, Biochemistry.

[20]  Stefan Kienle,et al.  Tolerance to Amino Acid Variations in Peptides Binding to the Major Histocompatibility Complex Class I Protein H-2Kb(*) , 1995, The Journal of Biological Chemistry.

[21]  H. Boehmer,et al.  Positive selection of antigen-specific T cells in thymus by restricting MHC molecules , 1988, Nature.

[22]  B. A. Fields,et al.  Molecular basis of antigen mimicry by an anti-idiotope , 1995, Nature.

[23]  W. Sebald,et al.  Two distinct functional sites of human interleukin 4 are identified by variants impaired in either receptor binding or receptor activation. , 1993, The EMBO journal.

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

[25]  M. Bevan.  Killer cells reactive to altered-self antigens can also be alloreactive. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Dean R. Madden,et al.  The three-dimensional structure of HLA-B27 at 2.1 Å resolution suggests a general mechanism for tight peptide binding to MHC , 1992, Cell.

[27]  David M. Kranz,et al.  Positive and negative selection of an antigen receptor on T cells in transgenic mice , 1988, Nature.

[28]  S. Kienle,et al.  Specificity and degeneracy of minor histocompatibility antigen-specific MHC-restricted CTL. , 1996, Journal of immunology.

[29]  M. Bevan,et al.  Major histocompatibility complex class I allele‐specific peptide libraries: Identification of peptides that mimic an H‐Y T cell epitope , 1994, European journal of immunology.

[30]  G J Williams,et al.  The Protein Data Bank: a computer-based archival file for macromolecular structures. , 1977, Journal of molecular biology.

[31]  P. A. Peterson,et al.  Emerging principles for the recognition of peptide antigens by MHC class I molecules. , 1992, Science.

[32]  R. Poljak,et al.  Three-dimensional structure of an idiotope–anti-idiotope complex , 1990, Nature.

[33]  Hidde L. Ploegh,et al.  Direct binding of peptide to empty MHC class I molecules on intact cells and in vitro , 1990, Cell.

[34]  H. Eisen,et al.  A naturally occurring peptide recognized by alloreactive CD8+ cytotoxic T lymphocytes in association with a class I MHC protein , 1992, Cell.

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

[36]  H. Rammensee,et al.  Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules , 1991, Nature.