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 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 CDR1alpha, an N-nucleotide-encoded Tyr94 in CDR3alpha, and a conserved His81 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 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., 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.
Gamerdinger
Katharina
K
Max-Planck-Institut für Immunbiologie, Stübeweg 51, D-79108 Freiburg, Germany.
Moulon
Corinne
C
Karp
David R
DR
Van Bergen
Jeroen
J
Koning
Frits
F
Wild
Doris
D
Pflugfelder
Ulrike
U
Weltzien
Hans Ulrich
HU
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D002460:Cell Line; D022801:Complementarity Determining Regions; D006684:HLA-DR Antigens / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D009532:Nickel / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*
D022801:Complementarity Determining Regions; D006684:HLA-DR Antigens; D011948:Receptors, Antigen, T-Cell; D009532:Nickel