BACKGROUND: Nickel is the most frequent cause of T cell-mediated allergic contact dermatitis worldwide. In vitro, CD4+ T cells from all donors respond to nickel but the involved αβ T cell receptor (TCR) repertoire has not been comprehensively analyzed. METHODS: We introduce CD154 (CD40L) upregulation as a fast, unbiased, and quantitative method to detect nickel-specific CD4+ T cells ex vivo in blood of clinically characterized allergic and non allergic donors. Naïve (CCR7+ CD45RA+) and memory (not naïve) CD154+ CD4+ T cells were analyzed by flow cytometry after 5 hours of stimulation with 200 µmol/L NiSO4 ., TCR α- and β-chains of sorted nickel-specific and control cells were studied by high-throughput sequencing. RESULTS: Stimulation of PBMCs with NiSO4 induced CD154 expression on ~0.1% (mean) of naïve and memory CD4+ T cells. In allergic donors with recent positive patch test, memory frequencies further increased ~13-fold and were associated with markers of in vivo activation. CD154 expression was TCR-mediated since single clones could be specifically restimulated. Among nickel-specific CD4+ T cells of allergic and non allergic donors, TCRs expressing the α-chain segment TRAV9-2 or a histidine in their α- or β-chain complementarity determining region 3 (CDR3) were highly overrepresented. CONCLUSIONS: Induced CD154 expression represents a reliable method to study nickel-specific CD4+ T cells. TCRs with particular features respond in all donors, while strongly increased blood frequencies indicate nickel allergy for some donors. Our approach may be extended to other contact allergens for the further development of diagnostic and predictive in vitro tests.

Center for Precision Genome Editing and Genetic Technologies for Biomedicine Pirogov Russian National Research Medical University Moscow Russia

Center of Molecular Medicine CEITEC Masaryk University Brno Czech Republic

Department of Chemical and Product Safety German Federal Institute for Risk Assessment Berlin Germany

Department of Dermatology and Allergy Ludwig Maximilian University Munich Germany

Department of Dermatology and Allergy University Hospital Schleswig Holstein Kiel Germany

Division of Allergy and Immunology Department of Dermatology Venerology and Allergy Charité Universitätsmedizin Berlin Berlin Germany

Division of Dermatology Queen's University Kingston ON Canada

Genomics of Adaptive Immunity Department Shemyakin Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Science Moscow Russia

Institute of Clinical Molecular Biology Christian Albrechts Universität zu Kiel Kiel Germany

Institute of Immunology Christian Albrechts Universität zu Kiel and Universitätsklinik Schleswig Holstein Kiel Germany

Sequencing Core Facility Max Planck Institute of Molecular Genetics Berlin Germany

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