Immunological mechanisms of metal allergies and the nickel-specific tcr-pmhc interface

Besides having physiological functions and general toxic effects, many metal ions can cause allergic reactions in humans. We here review the immune events involved in the mediation of metal allergies. We focus on nickel (Ni), cobalt (Co) and palladium (Pd), because these allergens are among the most prevalent sensitizers (Ni, Co) and immediate neighbors in the periodic table of the chemical elements. Co-sensitization between Ni and the other two metals is frequent while the knowledge on a possible immunological cross-reactivity using in vivo and in vitro approaches remains limited. At the center of an allergic reaction lies the capability of a metal allergen to form T cell epitopes that are recognized by specific T cell receptors (TCR). Technological advances such as activation-induced marker assays and TCR high-throughput sequencing recently provided new insights into the interaction of Ni²⁺ with the αβ TCR-peptide-major histocompatibility complex (pMHC) interface. Ni²⁺ functionally binds to the TCR gene segment TRAV9-2 or a histidine in the complementarity determining region 3 (CDR3), the main antigen binding region. Thus, we overview known, newly identified and hypothesized mechanisms of metal-specific T cell activation and discuss current knowledge on cross-reactivity.