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

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 a 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 Tyr(29) in CDR1alpha, an N-nucleotide-encoded Tyr(94) in CDR3alpha, and a conserved His(81) in the HLA-DR beta 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 a chain to His(81) 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., CDR3alpha-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.