A structural basis for immunodominant human T cell receptor recognition

The anti-influenza CD8+ T cell response in HLA-A2–positive adults is almost exclusively directed at residues 58–66 of the virus matrix protein (MP(58–66)). Vβ17Vα10.2 T cell receptors (TCRs) containing a conserved arginine-serine-serine sequence in complementarity determining region 3 (CDR3) of the Vβ segment dominate this response. To investigate the molecular basis of immunodominant selection in an outbred population, we have determined the crystal structure of Vβ17Vα10.2 in complex with MP(58–66)–HLA-A2 at a resolution of 1.4 Å. We show that, whereas the TCR typically fits over an exposed side chain of the peptide, in this structure MP(58–66) exposes only main chain atoms. This distinctive orientation of Vβ17Vα10.2, which is almost orthogonal to the peptide-binding groove of HLA-A2, facilitates insertion of the conserved arginine in Vβ CDR3 into a notch in the surface of MP(58–66)–HLA-A2. This previously unknown binding mode underlies the immunodominant T cell response.

[1]  J. Bell,et al.  Human HLA-A0201-restricted cytotoxic T lymphocyte recognition of influenza A is dominated by T cells bearing the V beta 17 gene segment , 1995, The Journal of experimental medicine.

[2]  K Schulten,et al.  VMD: visual molecular dynamics. , 1996, Journal of molecular graphics.

[3]  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.

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

[5]  V. Engelhard,et al.  Diversity and dominance among TCR recognizing HLA-A2.1+ influenza matrix peptide in human MHC class I transgenic mice. , 1994, Journal of immunology.

[6]  R J Read,et al.  Crystallography & NMR system: A new software suite for macromolecular structure determination. , 1998, Acta crystallographica. Section D, Biological crystallography.

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

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

[9]  J. Bell,et al.  Extensive conservation of alpha and beta chains of the human T-cell antigen receptor recognizing HLA-A2 and influenza A matrix peptide. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[10]  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.

[11]  M. Zambon,et al.  Influenza A antigen exposure selects dominant Vbeta17+ TCR in human CD8+ cytotoxic T cell responses. , 2001, International immunology.

[12]  C R Kissinger,et al.  Rapid automated molecular replacement by evolutionary search. , 1999, Acta crystallographica. Section D, Biological crystallography.

[13]  J. Thornton,et al.  PROCHECK: a program to check the stereochemical quality of protein structures , 1993 .

[14]  J. Yewdell,et al.  Immunodominance in major histocompatibility complex class I-restricted T lymphocyte responses. , 1999, Annual review of immunology.

[15]  D J Moss,et al.  Dominant selection of an invariant T cell antigen receptor in response to persistent infection by Epstein-Barr virus , 1994, The Journal of experimental medicine.

[16]  R M Esnouf,et al.  Further additions to MolScript version 1.4, including reading and contouring of electron-density maps. , 1999, Acta crystallographica. Section D, Biological crystallography.

[17]  E A Merritt,et al.  Raster3D Version 2.0. A program for photorealistic molecular graphics. , 1994, Acta crystallographica. Section D, Biological crystallography.

[18]  A. McMichael,et al.  Cytotoxic T lymphocytes recognize a fragment of influenza virus matrix protein in association with HLA-A2 , 1987, Nature.

[19]  H. Wolfson,et al.  Shape complementarity at protein–protein interfaces , 1994, Biopolymers.

[20]  R. Moots,et al.  Identification of the nonamer peptide from influenza A matrix protein and the role of pockets of HLA‐A2 in its recognition by cytotoxic T lymphocytes , 1992, European journal of immunology.

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

[22]  D. Wiley,et al.  Five viral peptide-HLA-A2 co-crystals. Simultaneous space group determination and X-ray data collection. , 1994, Journal of Molecular Biology.

[23]  R A Sayle,et al.  RASMOL: biomolecular graphics for all. , 1995, Trends in biochemical sciences.

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

[25]  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.

[26]  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.

[27]  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.

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

[29]  V. Engelhard,et al.  Definition of a human T cell epitope from influenza A non-structural protein 1 using HLA-A2.1 transgenic mice. , 1995, International immunology.