The Journal of Experimental Medicine
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Published 19 May 2003. doi:10.1084/jem.20030121
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© Rockefeller University Press, 0022-1007/2003/5/1345 $5.00
The Journal of Experimental Medicine, Volume 197, Number 10, 1345-1353

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



Katharina Gamerdinger1,2, Corinne Moulon1, David R. Karp3, Jeroen van Bergen4, Frits Koning4, Doris Wild1, Ulrike Pflugfelder1 and Hans Ulrich Weltzien1

1 Max-Planck-Institut für Immunbiologie, D-79108 Freiburg, Germany
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 {alpha} 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{alpha}, an N-nucleotide–encoded Tyr94 in CDR3{alpha}, 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 {alpha} 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{alpha}-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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