T-cell receptor (TCR) interaction with peptides that mimic nickel offers insight into nickel contact allergy

Abstract

T cell-mediated allergy to Ni++ is one of the most common forms of allergic contact dermatitis, but how the T-cell receptor (TCR) recognizes Ni ++ is unknown. We studied a TCR from an allergic patient that recognizes Ni ++ bound to the MHCII molecule DR52c containing an unknown self-peptide. We identified mimotope peptides that can replace both the self-peptide and Ni ++ in this ligand. They share a p7 lysine whose εNH 2 group is surface-exposed when bound to DR52c. Whereas the TCR uses germ-line complementary-determining region (CDR)1/2 amino acids to dock in the conventional diagonal mode on the mimotope-DR52c complex, the interface is dominated by the TCR Vβ CDR3 interaction with the p7 lysine. Mutations in the TCR CDR loops have similar effects on the T-cell response to either the mimotope or Ni ++ ligand. We suggest that the mimotope p7 lysine mimics Ni ++ in the natural TCR ligand and that MHCII β-chain flexibility in the area around the peptide p7 position forms a common site for cation binding in metal allergies.antigen presentation | hypersensitivity | peptide display library | crystal structure | metal recognition T -cell receptors (TCRs) made up of α-and β-chains have a very large number of ligands, including self-and foreign peptides, superantigens, lipids, small organic haptens, and metal ions. These ligands usually react with TCRs when they are bound to major histocompatibility complex (MHC) proteins. TCRs usually bind MHC/peptide combinations in similar orientations such that the TCR is aligned diagonally across the MHC/peptide, with the Vβ region of the TCR placed over the α1 α-helix of the MHCI heavy chain or of the MHCII α-chain and the Vα region placed over the α2 α-helix of the MHCI heavy chain or the β1 α-helix of the MHCII β-chain (1, 2). We (1, 3-5) and others (6-8) have suggested that germ line-encoded residues in the complementary-determining region (CDR)1 and CDR2 loops of the TCR variable regions are evolutionarily conserved for interaction with the MHC. These residues are also involved when natural killer T (NKT) cells recognize glycolipids bound to the nonclassical MHCI protein CD1d, and even when T cells recognize the non-MHC protein CD155 (9).It is noteworthy, however, that the presence of these evolutionarily conserved amino acids does not assure the conventional diagonal docking mode for TCRs on MHC molecules. For example, the NKT TCRs have a unique docking mode on CD1d (10, 11): Protein superantigens bridge TCRs to MHCII in a manner that prevents conventional TCR-MHCII interaction (12), and TCRs often dock to autoantigen peptides bound to MHCII in unusual orientations (13,14). Thus, in cases in which the structural details of the interaction between the TCR and its target are not known, we cannot be certain that the interaction will occur with the TCR in its usual orientation on MHC or not. Such is the case for the recognition of metal ions by TCRs (15 ++ when a particular unknown peptide(s) is bound to DR52c (18). Here, using a display library method we have previously describe...

Accumulation of metal-specific T cells in inflamed skin in a novel murine model of Chromium-induced allergic contact dermatitis

“…This difference was explained by the TCR footprint being dominated by the TCRb chain and b1 a-helix residues of HLA-DP2. Yin et al also reported CDR3b had a major role in recognition of human Nickel-self natural ligand [46]. In contrast with these reports, we observed diverse CDR3b sequences in Cr-induced ACD mice.…”

“…It was reported that activation of Ni-specific SE9 T cells depended on Thr residues in CDR1a and CDR3a [47]. Also, Ni-specific ANi2.3 interactions depended on Tyr and Thr residues in CDR1a and a Phe residue in CDR2a, and that ANi2.3 has an Arg-Asp-Gly-Tyr (RDGY) motif in CDR3b [46]. In this study, we did not identify a motif for Crbinding in CDR3a of VA11-1 but interestingly, shared TCR clonotypes contained Glu, Thr, His, Arg, and Tyr residues that have the potential to interact with Cr ions.…”

Structural aspects of molecular recognition in the immune system. Part I: Acquired immunity (IUPAC Technical Report)

“…In the unidentified endogenous peptide associated with nickel allergy, a bound Ni 2+ ion may replace the ε-NH 2 group. From Yin et al [74]. …”

“…It is generally thought that the metal ion is bound to a self-peptide presented by an MHC molecule. The CD4 + T cell, ANi2.3, contains a Vβ17 region that is over-represented in patients suffering from severe Ni contact hypersensitivity [74]. ANi2.3 αβTCR reacts with Ni 2+ in the context of an unknown self-peptide bound to an MHC class II molecule, HLA-DR52c.…”

“…ANi2.3 αβTCR reacts with Ni 2+ in the context of an unknown self-peptide bound to an MHC class II molecule, HLA-DR52c. Random screening of nine-amino acid-long peptide libraries identified sequences that caused the ANi2.3 TCR to bind to HLA-DR52c in the absence of Ni 2 β, and these peptides had in common a Lys residue at position 7, with an orientation that exposed the Lys ε-amino group [74]. It is proposed that the positive charge of the ε-amino group serves as a mimotope of the Ni (a) While the overall structure of the XV19 TCR-sulfatide/CD1d complex resembles that of a type I NKT TCR in complex with α-GalCer/CD1d (Fig.…”