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A New Type of Metal Recognition by Human T Cells : Contact Residues for Peptide-independent Bridging of T Cell Receptor and Major Histocompatibility Complex by Nickel
2 Fakultät für Biologie, Universität Freiburg, D-79104 Freiburg, Germany
3 Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390
4 Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, Netherlands
Address correspondence to H.U. Weltzien, Max-Planck-Institut für Immunbiologie, Stübeweg 51, D-79108 Freiburg, Germany. Phone: 49-761-5108-531; Fax: 49-761-5108-534; E-mail: weltzien{at}immunbio.mpg.de
In spite of high frequencies of metal allergies, the structural basis for major histocompatibility complex (MHC)-restricted metal recognition is among the unanswered questions in the field of T cell activation. For the human T cell clone SE9, we have identified potential Ni contact sites in the T cell receptor (TCR) and the restricting human histocompatibility leukocyte antigen (HLA)-DR structure. The specificity of this HLA-DR–promiscuous VA22/VB17+ TCR is primarily harbored in its
chain. Ni reactivity is neither dependent on protein processing in antigen-presenting cells nor affected by the nature of HLA-DR–associated peptides. However, SE9 activation by Ni crucially depends on Tyr29 in CDR1, an N-nucleotide–encoded Tyr94 in CDR3, and a conserved His81 in the HLA-DR ß chain. These data indicate that labile, nonactivating complexes between the SE9 TCR and most HLA-DR/peptide conjugates might supply sterically optimized coordination sites for Ni ions, three of which were identified in this study. In such complexes Ni may effectively bridge the TCR chain to His81 of most DR molecules. Thus, in analogy to superantigens, Ni may directly link TCR and MHC in a peptide-independent manner. However, unlike superantigens, Ni requires idiotypic, i.e., CDR3-determined TCR amino acids. This new type of TCR–MHC linkage might explain the high frequency of Ni-reactive T cells in the human population.
Key Words: hypersensitivity • antigen presentation • hapten • T cell receptor • mutation
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