{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T20:43:37Z","timestamp":1781037817800,"version":"3.54.1"},"reference-count":194,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T00:00:00Z","timestamp":1730851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"BfR","award":["BfR-CPS-23-1322-848"],"award-info":[{"award-number":["BfR-CPS-23-1322-848"]}]},{"name":"BfR","award":["500312706"],"award-info":[{"award-number":["500312706"]}]},{"DOI":"10.13039\/501100001659","name":"DFG","doi-asserted-by":"publisher","award":["BfR-CPS-23-1322-848"],"award-info":[{"award-number":["BfR-CPS-23-1322-848"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"DFG","doi-asserted-by":"publisher","award":["500312706"],"award-info":[{"award-number":["500312706"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>T cell activation is the final key event (KE4) in the adverse outcome pathway (AOP) of skin sensitization. However, validated new approach methodologies (NAMs) for evaluating this step are missing. Accordingly, chemicals that activate an unusually high frequency of T cells, as does the most prevalent metal allergen nickel, are not yet identified in a regulatory context. T cell reactivity to chemical sensitizers might be especially relevant in real-life scenarios, where skin injury, co-exposure to irritants in chemical mixtures, or infections may trigger the heterologous innate immune stimulation necessary to induce adaptive T cell responses. Additionally, cross-reactivity, which underlies cross-allergies, can only be assessed by T cell tests. To date, several experimental T cell tests are available that use primary na\u00efve and memory CD4+ and CD8+ T cells from human blood. These include priming and lymphocyte proliferation tests and, most recently, activation-induced marker (AIM) assays. All approaches are challenged by chemical-mediated toxicity, inefficient or unknown generation of T cell epitopes, and a low throughput. Here, we summarize solutions and strategies to confirm in vitro T cell signals. Broader application and standardization are necessary to possibly define chemical applicability domains and to strengthen the role of T cell tests in regulatory risk assessment.<\/jats:p>","DOI":"10.3390\/toxics12110802","type":"journal-article","created":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T06:27:39Z","timestamp":1730874459000},"page":"802","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Chemical-Specific T Cell Tests Aim to Bridge a Gap in Skin Sensitization Evaluation"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9504-5559","authenticated-orcid":false,"given":"Nele","family":"Fritsch","sequence":"first","affiliation":[{"name":"German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Dermatotoxicology Study Centre, 10589 Berlin, Germany"},{"name":"Institute of Biotechnology, Technical University of Berlin, 10115 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5483-1366","authenticated-orcid":false,"given":"Marina","family":"Aparicio-Soto","sequence":"additional","affiliation":[{"name":"German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Dermatotoxicology Study Centre, 10589 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4938-7288","authenticated-orcid":false,"given":"Caterina","family":"Curato","sequence":"additional","affiliation":[{"name":"German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Dermatotoxicology Study Centre, 10589 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Riedel","sequence":"additional","affiliation":[{"name":"German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Dermatotoxicology Study Centre, 10589 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9655-681X","authenticated-orcid":false,"given":"Hermann-Josef","family":"Thierse","sequence":"additional","affiliation":[{"name":"German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Dermatotoxicology Study Centre, 10589 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Luch","sequence":"additional","affiliation":[{"name":"German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Dermatotoxicology Study Centre, 10589 Berlin, Germany"},{"name":"Institute of Pharmacy, Freie Universit\u00e4t Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0380-1594","authenticated-orcid":false,"given":"Katherina","family":"Siewert","sequence":"additional","affiliation":[{"name":"German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Dermatotoxicology Study Centre, 10589 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/S1567-5769(01)00173-4","article-title":"Allergic contact dermatitis","volume":"2","author":"Kimber","year":"2002","journal-title":"Int. Immunopharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1111\/j.1600-0625.2012.01471.x","article-title":"Contact dermatitis: From pathomechanisms to immunotoxicology","volume":"21","author":"Martin","year":"2012","journal-title":"Exp. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41572-021-00271-4","article-title":"Contact dermatitis","volume":"7","author":"Scheinman","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1111\/j.1600-0536.2006.01058.x","article-title":"Contact allergy epidemics and their controls","volume":"56","author":"Thyssen","year":"2007","journal-title":"Contact Dermat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1111\/jdv.15875","article-title":"The epidemic of methylisothiazolinone contact allergy in Europe: Follow-up on changing exposures","volume":"34","author":"Uter","year":"2020","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/cod.13119","article-title":"Prevalence of contact allergy in the general population: A systematic review and meta-analysis","volume":"80","author":"Alinaghi","year":"2019","journal-title":"Contact Dermat."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Uter, W., Werfel, T., Lepoittevin, J.P., and White, I.R. (2020). Contact Allergy-Emerging Allergens and Public Health Impact. Int. J. Environ. Res. Public. Health, 17.","DOI":"10.3390\/ijerph17072404"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1001\/archderm.1965.01600080079017","article-title":"Delayed Contact Hypersensitivity in the Guinea Pig","volume":"91","author":"Buehler","year":"1965","journal-title":"Arch. Dermatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/jid.1969.42","article-title":"The identification of contact allergens by animal assay. The guinea pig maximization test","volume":"52","author":"Magnusson","year":"1969","journal-title":"J. Investig. Dermatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1007\/BF00278640","article-title":"A murine local lymph node assay for the identification of contact allergens. Assay development and results of an initial validation study","volume":"63","author":"Kimber","year":"1989","journal-title":"Arch. Toxicol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1080\/10408444.2023.2240852","article-title":"International regulatory uses of acute systemic toxicity data and integration of new approach methodologies","volume":"53","author":"Strickland","year":"2023","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1001\/archderm.1952.01530310041005","article-title":"Procedure for evaluating skin-sensitizing power of new materials","volume":"66","author":"Brunner","year":"1952","journal-title":"AMA Arch. Derm. Syphilol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bialas, I., Zelent-Kraciuk, S., and Jurowski, K. (2023). The Skin Sensitisation of Cosmetic Ingredients: Review of Actual Regulatory Status. Toxics, 11.","DOI":"10.3390\/toxics11040392"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1080\/15569520902938032","article-title":"The human repeated insult patch test in the 21st century: A commentary","volume":"28","author":"Basketter","year":"2009","journal-title":"Cutan. Ocul. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.yrtph.2007.11.004","article-title":"The Research Institute for Fragrance Materials\u2019 human repeated insult patch test protocol","volume":"52","author":"Politano","year":"2008","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1172\/JCI107376","article-title":"Lymphocyte transformation during dinitrochlorobenzene contact sensitization. An in vitro and in vivo evaluation of the primary immune response in man","volume":"52","author":"Miller","year":"1973","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/978-1-4615-2930-9_35","article-title":"Human in vitro T cell sensitization using hapten-modified epidermal Langerhans cells","volume":"329","author":"Moulon","year":"1993","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1016\/j.tiv.2012.08.007","article-title":"Human T cell priming assay (hTCPA) for the identification of contact allergens based on naive T cells and DC--IFN-gamma and TNF-alpha readout","volume":"27","author":"Richter","year":"2013","journal-title":"Toxicol. Vitr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2574","DOI":"10.1111\/all.14322","article-title":"TCRs with segment TRAV9-2 or a CDR3 histidine are overrepresented among nickel-specific CD4+ T cells","volume":"75","author":"Riedel","year":"2020","journal-title":"Allergy"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"087024","DOI":"10.1289\/EHP1435","article-title":"Has Toxicity Testing Moved into the 21st Century? A Survey and Analysis of Perceptions in the Field of Toxicology","volume":"125","author":"Zaunbrecher","year":"2017","journal-title":"Environ. Health Perspect."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"105426","DOI":"10.1016\/j.yrtph.2023.105426","article-title":"OECD harmonised template 201: Structuring and reporting mechanistic information to foster the integration of new approach methodologies for hazard and risk assessment of chemicals","volume":"142","author":"Carnesecchi","year":"2023","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.1021\/tx500345j","article-title":"Defining molecular initiating events in the adverse outcome pathway framework for risk assessment","volume":"27","author":"Allen","year":"2014","journal-title":"Chem. Res. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Stucki, A.O., Barton-Maclaren, T.S., Bhuller, Y., Henriquez, J.E., Henry, T.R., Hirn, C., Miller-Holt, J., Nagy, E.G., Perron, M.M., and Ratzlaff, D.E. (2022). Use of new approach methodologies (NAMs) to meet regulatory requirements for the assessment of industrial chemicals and pesticides for effects on human health. Front. Toxicol., 4.","DOI":"10.3389\/ftox.2022.964553"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gadarowska, D., Kalka, J., Daniel-Wojcik, A., and Mrzyk, I. (2022). Alternative Methods for Skin-Sensitization Assessment. Toxics, 10.","DOI":"10.3390\/toxics10120740"},{"key":"ref_25","unstructured":"OECD (2012). The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins, OECD. Part 1: Scientific Evidence. ENV\/JM\/MONO(2012)10\/PART1."},{"key":"ref_26","first-page":"101","article-title":"Correlation of contact sensitizer potency with T cell frequency and TCR repertoire diversity","volume":"104","author":"Esser","year":"2014","journal-title":"Exp. Suppl."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1002\/jat.3572","article-title":"Integrated decision strategies for skin sensitization hazard","volume":"38","author":"Strickland","year":"2016","journal-title":"J. Appl. Toxicol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"473","DOI":"10.14573\/altex.2013.4.473","article-title":"From pathways to people: Applying the adverse outcome pathway (AOP) for skin sensitization to risk assessment","volume":"30","author":"MacKay","year":"2013","journal-title":"ALTEX"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/cod.13167","article-title":"Skin sensitization: Uncertainties, challenges, and opportunities for improved risk assessment","volume":"80","author":"Gilmour","year":"2019","journal-title":"Contact Dermat."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4171","DOI":"10.1007\/s00018-010-0495-3","article-title":"T-cell recognition of chemicals, protein allergens and drugs: Towards the development of in vitro assays","volume":"67","author":"Martin","year":"2010","journal-title":"Cell Mol. Life. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.tox.2011.11.007","article-title":"Allergic contact dermatitis: A commentary on the relationship between T lymphocytes and skin sensitising potency","volume":"291","author":"Kimber","year":"2012","journal-title":"Toxicology"},{"key":"ref_32","first-page":"179","article-title":"State-of-the-art and new options to assess T cell activation by skin sensitizers: Cosmetics Europe Workshop","volume":"35","author":"Kuhnl","year":"2018","journal-title":"Altern. Anim. Exp."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/334395a0","article-title":"T-cell antigen receptor genes and T-cell recognition","volume":"334","author":"Davis","year":"1988","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nature22383","article-title":"Quantifiable predictive features define epitope-specific T cell receptor repertoires","volume":"547","author":"Dash","year":"2017","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4099","DOI":"10.1182\/blood-2009-04-217604","article-title":"Comprehensive assessment of T-cell receptor beta-chain diversity in alphabeta T cells","volume":"114","author":"Robins","year":"2009","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Riedel, F., Aparicio-Soto, M., Curato, C., Thierse, H.J., Siewert, K., and Luch, A. (2021). Immunological Mechanisms of Metal Allergies and the Nickel-Specific TCR-pMHC Interface. Int. J. Environ. Res. Public. Health, 18.","DOI":"10.3390\/ijerph182010867"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/nri3279","article-title":"Why must T cells be cross-reactive?","volume":"12","author":"Sewell","year":"2012","journal-title":"Nat. Rev. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/j.1600-065X.2012.01165.x","article-title":"Structural and dynamic control of T-cell receptor specificity, cross-reactivity, and binding mechanism","volume":"250","author":"Baker","year":"2012","journal-title":"Immunol. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1111\/imr.12095","article-title":"Antiviral memory phenotype T cells in unexposed adults","volume":"255","author":"Su","year":"2013","journal-title":"Immunol. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1002\/cyto.a.22317","article-title":"Flow-cytometric analysis of rare antigen-specific T cells","volume":"83","author":"Bacher","year":"2013","journal-title":"Cytom. A"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1146\/annurev.immunol.25.022106.141548","article-title":"Effector and memory CTL differentiation","volume":"25","author":"Williams","year":"2007","journal-title":"Annu. Rev. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5005","DOI":"10.4049\/jimmunol.1600005","article-title":"Dynamics of Individual T Cell Repertoires: From Cord Blood to Centenarians","volume":"196","author":"Britanova","year":"2016","journal-title":"J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/s41590-022-01395-9","article-title":"Tissue adaptation and clonal segregation of human memory T cells in barrier sites","volume":"24","author":"Poon","year":"2023","journal-title":"Nat. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1146\/annurev.immunol.23.021704.115658","article-title":"How TCRs bind MHCs, peptides, and coreceptors","volume":"24","author":"Rudolph","year":"2006","journal-title":"Annu. Rev. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Aparicio-Soto, M., Curato, C., Riedel, F., Thierse, H.J., Luch, A., and Siewert, K. (2021). In Vitro Monitoring of Human T Cell Responses to Skin Sensitizing Chemicals-A Systematic Review. Cells, 11.","DOI":"10.3390\/cells11010083"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/0300-483X(95)03253-C","article-title":"T cell immune responses to haptens. Structural models for allergic and autoimmune reactions","volume":"107","author":"Weltzien","year":"1996","journal-title":"Toxicology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1080\/17425255.2018.1441285","article-title":"Implications of HLA-allele associations for the study of type IV drug hypersensitivity reactions","volume":"14","author":"Sullivan","year":"2018","journal-title":"Expert. Opin. Drug. Metab. Toxicol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2623","DOI":"10.1021\/acs.chemrestox.0c00271","article-title":"Characterizing Adduct Formation of Electrophilic Skin Allergens with Human Serum Albumin and Hemoglobin","volume":"33","author":"Ndreu","year":"2020","journal-title":"Chem. Res. Toxicol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1111\/all.13765","article-title":"Immune pathomechanism and classification of drug hypersensitivity","volume":"74","author":"Pichler","year":"2019","journal-title":"Allergy"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/cod.14037","article-title":"Electron paramagnetic resonance and spin trapping to detect free radicals from allergenic hydroperoxides in contact with the skin: From the molecule to the tissue","volume":"86","author":"Vileno","year":"2022","journal-title":"Contact Dermat."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1111\/all.15494","article-title":"Unique and common TCR repertoire features of Ni2+-, Co2+-, and Pd2+-specific human CD154 + CD4+ T cells","volume":"78","author":"Riedel","year":"2023","journal-title":"Allergy"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Curato, C., Aparicio-Soto, M., Riedel, F., Wehl, I., Basaran, A., Abbas, A., Thierse, H.J., Luch, A., and Siewert, K. (2022). Frequencies and TCR Repertoires of Human 2,4,6-Trinitrobenzenesulfonic Acid-specific T Cells. Front. Toxicol., 4.","DOI":"10.3389\/ftox.2022.827109"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1034\/j.1600-0625.2003.120110.x","article-title":"A high frequency of allergen-specific CD8+ Tc1 cells is associated with the murine immune response to the contact sensitizer trinitrophenyl","volume":"12","author":"Martin","year":"2003","journal-title":"Exp. Dermatol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2788","DOI":"10.1002\/eji.1830251012","article-title":"Carrier-reactive hapten-specific cytotoxic T lymphocyte clones originate from a highly preselected T cell repertoire: Implications for chemical-induced self-reactivity","volume":"25","author":"Martin","year":"1995","journal-title":"Eur. J. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/icb.2010.139","article-title":"Bias in the alphabeta T-cell repertoire: Implications for disease pathogenesis and vaccination","volume":"89","author":"Miles","year":"2011","journal-title":"Immunol. Cell Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e54747","DOI":"10.7554\/eLife.54747","article-title":"The clonal structure and dynamics of the human T cell response to an organic chemical hapten","volume":"10","author":"Ronel","year":"2021","journal-title":"Elife"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/cr.2012.1","article-title":"Determinants of public T cell responses","volume":"22","author":"Li","year":"2012","journal-title":"Cell Res."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Ruiz Ortega, M., Spisak, N., Mora, T., and Walczak, A.M. (2023). Modeling and predicting the overlap of B- and T-cell receptor repertoires in healthy and SARS-CoV-2 infected individuals. PLoS Genet., 19.","DOI":"10.1371\/journal.pgen.1010652"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1007\/s11764-021-01148-x","article-title":"Correction to: Evaluation of an electronic psycho-oncological adaptive screening program (EPAS) with immediate patient feedback: Findings from a German cluster intervention study","volume":"17","author":"Esser","year":"2023","journal-title":"J. Cancer Surviv."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1111\/j.1600-0536.2011.01945.x","article-title":"Enhanced sensitization and elicitation responses caused by mixtures of common fragrance allergens","volume":"65","author":"Bonefeld","year":"2011","journal-title":"Contact Dermat."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1111\/exd.12634","article-title":"Nickel acts as an adjuvant during cobalt sensitization","volume":"24","author":"Bonefeld","year":"2015","journal-title":"Exp. Dermatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/0300-483X(93)90148-L","article-title":"Influence of sodium lauryl sulphate on 2,4-dinitrochlorobenzene-induced lymph node activation","volume":"77","author":"Cumberbatch","year":"1993","journal-title":"Toxicology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1097\/DER.0000000000000666","article-title":"Nickel: Intrinsic Skin Sensitization Potency and Relation to Prevalence of Contact Allergy","volume":"32","author":"Basketter","year":"2021","journal-title":"Dermatitis"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"H\u00f6per, T., Siewert, K., Dumit, V.I., von Bergen, M., Schubert, K., and Haase, A. (2021). The Contact Allergen NiSO(4) Triggers a Distinct Molecular Response in Primary Human Dendritic Cells Compared to Bacterial LPS. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.644700"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1038\/ni.1919","article-title":"Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel","volume":"11","author":"Schmidt","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1038\/nm.2078","article-title":"Epidermal injury and infection during poxvirus immunization is crucial for the generation of highly protective T cell-mediated immunity","volume":"16","author":"Liu","year":"2010","journal-title":"Nat. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/cod.12983","article-title":"Prevalence of contact allergy to metals in the European general population with a focus on nickel and piercings: The EDEN Fragrance Study","volume":"79","author":"Schuttelaar","year":"2018","journal-title":"Contact Dermat."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/S0887-2333(00)00043-6","article-title":"In vitro human T cell sensitization to haptens by monocyte-derived dendritic cells","volume":"14","author":"Guironnet","year":"2000","journal-title":"Toxicol. Vitr."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1038\/jid.2008.15","article-title":"Depletion of human peripheral blood lymphocytes in CD25+ cells allows for the sensitive in vitro screening of contact allergens","volume":"128","author":"Vocanson","year":"2008","journal-title":"J. Investig. Dermatol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1093\/toxsci\/kfq209","article-title":"Tracking human contact allergens: From mass spectrometric identification of peptide-bound reactive small chemicals to chemical-specific naive human T-cell priming","volume":"117","author":"Dietz","year":"2010","journal-title":"Toxicol. Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1021\/acs.chemrestox.5b00294","article-title":"In Vitro Priming of Na\u00efve T-cells with p-Phenylenediamine and Bandrowski\u2019s Base","volume":"28","author":"Gibson","year":"2015","journal-title":"Chem. Res. Toxicol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1111\/jdv.14931","article-title":"Cytokine patterns in vitro, in particular IL-5\/IL-8 ratio, to detect patients with nickel contact allergy","volume":"32","author":"Summer","year":"2018","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_73","first-page":"420","article-title":"Lymphocyte transformation in mercury hypersensitivity. Non-specific transformation due to mercury compounds","volume":"234","author":"Schopf","year":"1969","journal-title":"Arch. Klin. Exp. Dermatol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1111\/j.1398-9995.2004.00547.x","article-title":"The lymphocyte transformation test in the diagnosis of drug hypersensitivity","volume":"59","author":"Pichler","year":"2004","journal-title":"Allergy"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/0091-6749(86)90083-7","article-title":"T cell reactivity to penicillin: Phenotypic analysis of in vitro activated cell subsets","volume":"78","author":"Koponen","year":"1986","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1038\/sj.jid.5701071","article-title":"Activation of T-cells from allergic patients and volunteers by p-phenylenediamine and Bandrowski\u2019s base","volume":"128","author":"Coulter","year":"2008","journal-title":"J. Investig. Dermatol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/jid.2009.187","article-title":"Measurement of CD4+ and CD8+ T-lymphocyte cytokine secretion and gene expression changes in p-phenylenediamine allergic patients and tolerant individuals","volume":"130","author":"Coulter","year":"2010","journal-title":"J. Investig. Dermatol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Bordignon, V., Palamara, F., Altomonte, G., Sperduti, I., Pietravalle, M., Cavallotti, C., Cordiali-Fei, P., Fuggetta, M.P., Cristaudo, A., and Ensoli, F. (2015). A laboratory test based on determination of cytokine profiles: A promising assay to identify exposition to contact allergens and predict the clinical outcome in occupational allergic contact dermatitis. BMC Immunol., 16.","DOI":"10.1186\/s12865-015-0066-3"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/0022-1759(93)90158-4","article-title":"Detection of intracellular cytokines by flow cytometry","volume":"159","author":"Jung","year":"1993","journal-title":"J. Immunol. Methods"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Saxena, A., Dagur, P.K., Desai, A., and McCoy, J.P. (2018). Ultrasensitive Quantification of Cytokine Proteins in Single Lymphocytes From Human Blood Following ex-vivo Stimulation. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02462"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/S1046-2023(03)00125-7","article-title":"Detection and enrichment of antigen-specific CD4+ and CD8+ T cells based on cytokine secretion","volume":"31","author":"Campbell","year":"2003","journal-title":"Methods"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1126\/science.274.5284.94","article-title":"Phenotypic analysis of antigen-specific T lymphocytes","volume":"274","author":"Altman","year":"1996","journal-title":"Science"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1084\/jem.20090504","article-title":"Human naive and memory CD4+ T cell repertoires specific for naturally processed antigens analyzed using libraries of amplified T cells","volume":"206","author":"Geiger","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1002\/jat.3197","article-title":"An in vitro human skin test for assessing sensitization potential","volume":"36","author":"Ahmed","year":"2016","journal-title":"J. Appl. Toxicol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.taap.2019.02.005","article-title":"Evaluation of a human in vitro skin test for predicting drug hypersensitivity reactions","volume":"369","author":"Ahmed","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1615\/CritRevImmunol.v37.i2-6.60","article-title":"Accessory Molecule and Costimulation Requirements for CD4 T Cell Response","volume":"37","author":"Croft","year":"2017","journal-title":"Crit. Rev. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3280","DOI":"10.4049\/jimmunol.157.8.3280","article-title":"Naive and effector CD4 T cells differ in their requirements for T cell receptor versus costimulatory signals","volume":"157","author":"Dubey","year":"1996","journal-title":"J. Immunol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1111\/j.1600-065X.2011.01011.x","article-title":"Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28\/ B7 family","volume":"241","author":"Esensten","year":"2011","journal-title":"Immunol. Rev."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1038\/s41590-023-01510-4","article-title":"CD4+ T cell memory","volume":"24","author":"Kunzli","year":"2023","journal-title":"Nat. Immunol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1084\/jem.20030448","article-title":"Regulation of dendritic cell migration to the draining lymph node: Impact on T lymphocyte traffic and priming","volume":"198","author":"Sebastiani","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_91","first-page":"89","article-title":"Human T cell priming assay: Depletion of peripheral blood lymphocytes in CD25+ cells improves the in vitro detection of weak allergen-specific T cells","volume":"104","author":"Vocanson","year":"2014","journal-title":"Exp. Suppl."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1084\/jem.179.4.1109","article-title":"Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte\/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha","volume":"179","author":"Sallusto","year":"1994","journal-title":"J. Exp. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/S0140-6736(67)91362-1","article-title":"Lymphocyte transformation in drug hypersensitivity","volume":"1","author":"Sarkany","year":"1967","journal-title":"Lancet"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Ganesan, N., Ronsmans, S., and Hoet, P. (2023). Methods to Assess Proliferation of Stimulated Human Lymphocytes In Vitro: A Narrative Review. Cells, 12.","DOI":"10.3390\/cells12030386"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/cod.12697","article-title":"In vitro human T cell responses to diphencyprone","volume":"76","author":"Friedmann","year":"2017","journal-title":"Contact Dermat."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1111\/j.1600-0625.2009.01043.x","article-title":"Para-phenylenediamine-specific lymphocyte activation test: A sensitive in vitro assay to detect para-phenylenediamine sensitization in patients with severe allergic reactions","volume":"19","author":"Kneilling","year":"2010","journal-title":"Exp. Dermatol."},{"key":"ref_97","first-page":"268","article-title":"Polyclonal T lymphocyte proliferation in drug lymphocyte activation test","volume":"127","author":"Martin","year":"2000","journal-title":"Ann. Dermatol. Venereol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"113036","DOI":"10.1016\/j.jim.2021.113036","article-title":"Lymphocyte transformation test: History and current approaches","volume":"493","author":"Sachs","year":"2021","journal-title":"J. Immunol. Methods"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"84","DOI":"10.3109\/1547691X.2015.1008656","article-title":"The lymphocyte transformation test in allergic contact dermatitis: New opportunities","volume":"13","author":"Popple","year":"2016","journal-title":"J. Immunotoxicol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1111\/j.1365-2222.2004.02045.x","article-title":"Analysis of effector and regulatory immune reactivity to nickel","volume":"34","author":"Rustemeyer","year":"2004","journal-title":"Clin. Exp. Allergy"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/s41467-019-13788-w","article-title":"Differential expansion of T central memory precursor and effector subsets is regulated by division speed","volume":"11","author":"Kretschmer","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_102","first-page":"259","article-title":"Direct comparison of ELISPOT and ELISA-based assays for detection of individual cytokine-secreting cells","volume":"13","author":"Tanguay","year":"1994","journal-title":"Lymphokine Cytokine Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1111\/j.1365-2133.2003.05750.x","article-title":"Methylisothiazolinones elicit increased production of both T helper (Th)1- and Th2-like cytokines by peripheral blood mononuclear cells from contact allergic individuals","volume":"149","author":"Masjedi","year":"2003","journal-title":"Br. J. Dermatol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/978-1-4939-7346-0_9","article-title":"Multiparameter Intracellular Cytokine Staining","volume":"1678","author":"Lovelace","year":"2018","journal-title":"Methods Mol. Biol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1111\/imcb.12636","article-title":"T-cell activation-induced marker assays in health and disease","volume":"101","author":"Poloni","year":"2023","journal-title":"Immunol. Cell Biol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1038\/nm1293","article-title":"A live-cell assay to detect antigen-specific CD4+ T cells with diverse cytokine profiles","volume":"11","author":"Chattopadhyay","year":"2005","journal-title":"Nat. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.taap.2017.05.020","article-title":"Using DR52c\/Ni2+ mimotope tetramers to detect Ni2+ reactive CD4+ T cells in patients with joint replacement failure","volume":"331","author":"Zhang","year":"2017","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e2000267","DOI":"10.1002\/pmic.202000267","article-title":"Drug hapten-specific T-cell activation: Current status and unanswered questions","volume":"21","author":"Adair","year":"2021","journal-title":"Proteomics"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Pastore, G., Carraro, M., Pettini, E., Nolfi, E., Medaglini, D., and Ciabattini, A. (2019). Optimized Protocol for the Detection of Multifunctional Epitope-Specific CD4+ T Cells Combining MHC-II Tetramer and Intracellular Cytokine Staining Technologies. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02304"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1111\/j.1365-2567.2007.02801.x","article-title":"Class II major histocompatibility complex tetramer staining: Progress, problems, and prospects","volume":"123","author":"Vollers","year":"2008","journal-title":"Immunology"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1038\/s41587-021-00893-9","article-title":"MHC class II tetramers engineered for enhanced binding to CD4 improve detection of antigen-specific T cells","volume":"39","author":"Dileepan","year":"2021","journal-title":"Nat. Biotechnol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/978-1-0716-2712-9_3","article-title":"Identification of Human Antigen-Specific T Cells Using Class II MHC Tetramer Staining and Enrichment","volume":"2574","author":"Pan","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Newell, E.W. (2013). Higher throughput methods of identifying T cell epitopes for studying outcomes of altered antigen processing and presentation. Front. Immunol., 4.","DOI":"10.3389\/fimmu.2013.00430"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1111\/tan.13789","article-title":"Peptide-MHC class I and class II tetramers: From flow to mass cytometry","volume":"95","author":"Christophersen","year":"2020","journal-title":"HLA"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.4049\/jimmunol.1102190","article-title":"Frequency of epitope-specific naive CD4+ T cells correlates with immunodominance in the human memory repertoire","volume":"188","author":"Kwok","year":"2012","journal-title":"J. Immunol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.4049\/jimmunol.1102398","article-title":"MHC class II tetramers","volume":"188","author":"Nepom","year":"2012","journal-title":"J. Immunol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.jim.2016.01.014","article-title":"T-cell libraries allow simple parallel generation of multiple peptide-specific human T-cell clones","volume":"430","author":"Theaker","year":"2016","journal-title":"J. Immunol. Methods"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.4049\/jimmunol.1800267","article-title":"Identification and Analysis of Islet Antigen-Specific CD8+ T Cells with T Cell Libraries","volume":"201","author":"Ogura","year":"2018","journal-title":"J. Immunol."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Ahmed, S.S., Ahmed, M.M., Ishaq, A., Freer, M., Stebbings, R., and Dickinson, A.M. (2024). An In Vitro Human Skin Test for Predicting Skin Sensitization and Adverse Immune Reactions to Biologics. Toxics, 12.","DOI":"10.3390\/toxics12060401"},{"key":"ref_120","first-page":"367","article-title":"Histopathology of graft-vs.-host reaction (GvHR) in human recipients of marrow from HL-A-matched sibling donors","volume":"6","author":"Lerner","year":"1974","journal-title":"Transpl. Proc."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"3967","DOI":"10.4049\/jimmunol.1202221","article-title":"Antigen-reactive T cell enrichment for direct, high-resolution analysis of the human naive and memory Th cell repertoire","volume":"190","author":"Bacher","year":"2013","journal-title":"J. Immunol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"100690","DOI":"10.1016\/j.crmeth.2023.100690","article-title":"Enhanced detection of antigen-specific T cells by a multiplexed AIM assay","volume":"4","author":"Lemieux","year":"2024","journal-title":"Cell Rep. Methods"},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Reiss, S., Baxter, A.E., Cirelli, K.M., Dan, J.M., Morou, A., Daigneault, A., Brassard, N., Silvestri, G., Routy, J.P., and Havenar-Daughton, C. (2017). Comparative analysis of activation induced marker (AIM) assays for sensitive identification of antigen-specific CD4 T cells. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0186998"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.imlet.2019.12.006","article-title":"Activation-induced surface proteins in the identification of antigen-responsive CD4 T cells","volume":"219","author":"Elias","year":"2020","journal-title":"Immunol. Lett."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1182\/blood-2006-11-056168","article-title":"Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specificities","volume":"110","author":"Wolfl","year":"2007","journal-title":"Blood"},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Bremser, A., Brack, M., and Izcue, A. (2015). Higher Sensitivity of Foxp3+ Treg Compared to Foxp3- Conventional T Cells to TCR-Independent Signals for CD69 Induction. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0137393"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1084\/jem.148.5.1440","article-title":"Peripheral human T cells sensitized in mixed leukocyte culture synthesize and express Ia-like antigens","volume":"148","author":"Evans","year":"1978","journal-title":"J. Exp. Med."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"3653","DOI":"10.1182\/blood-2007-07-101600","article-title":"Antigen-induced clustering of surface CD38 and recruitment of intracellular CD38 to the immunologic synapse","volume":"111","author":"Munoz","year":"2008","journal-title":"Blood"},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Ghosh, A., Khanam, A., Ray, K., Mathur, P., Subramanian, A., Poonia, B., and Kottilil, S. (2023). CD38: An ecto-enzyme with functional diversity in T cells. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1146791"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1182\/blood-2013-02-483586","article-title":"CD40L expression permits CD8+ T cells to execute immunologic helper functions","volume":"122","author":"Frentsch","year":"2013","journal-title":"Blood"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"3500","DOI":"10.4049\/jimmunol.164.7.3500","article-title":"IL-2 and IL-15 regulate CD154 expression on activated CD4 T cells","volume":"164","author":"Skov","year":"2000","journal-title":"J. Immunol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1038\/nm1292","article-title":"Direct access to CD4+ T cells specific for defined antigens according to CD154 expression","volume":"11","author":"Frentsch","year":"2005","journal-title":"Nat. Med."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1146\/annurev.immunol.23.021704.115839","article-title":"TNF\/TNFR family members in costimulation of T cell responses","volume":"23","author":"Watts","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.4049\/jimmunol.167.3.1313","article-title":"4-1BB ligand induces cell division, sustains survival, and enhances effector function of CD4 and CD8 T cells with similar efficacy","volume":"167","author":"Cannons","year":"2001","journal-title":"J. Immunol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"5985","DOI":"10.4049\/jimmunol.1201090","article-title":"A converse 4-1BB and CD40 ligand expression pattern delineates activated regulatory T cells (Treg) and conventional T cells enabling direct isolation of alloantigen-reactive natural Foxp3+ Treg","volume":"189","author":"Schoenbrunn","year":"2012","journal-title":"J. Immunol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jim.2005.05.002","article-title":"Isolation of viable antigen-specific CD4 T cells by CD40L surface trapping","volume":"302","author":"Cohen","year":"2005","journal-title":"J. Immunol. Methods"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.4049\/jimmunol.133.4.1710","article-title":"Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67","volume":"133","author":"Gerdes","year":"1984","journal-title":"J. Immunol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1084\/jem.181.5.1935","article-title":"Circulating allergen-reactive T cells from patients with atopic dermatitis and allergic contact dermatitis express the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen","volume":"181","author":"Picker","year":"1995","journal-title":"J. Exp. Med."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1046\/j.1523-1747.1998.00334.x","article-title":"Patients with allergic contact dermatitis to nickel and nonallergic individuals display different nickel-specific T cell responses. Evidence for the presence of effector CD8+ and regulatory CD4+ T cells","volume":"111","author":"Cavani","year":"1998","journal-title":"J. Investig. Dermatol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.coph.2015.04.005","article-title":"New technologies for monitoring human antigen-specific T cells and regulatory T cells by flow-cytometry","volume":"23","author":"Bacher","year":"2015","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/978-1-0716-1311-5_12","article-title":"Flow Cytometric Characterization of Human Antigen-Reactive T-Helper Cells","volume":"2285","author":"Saggau","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"5760","DOI":"10.4049\/jimmunol.171.11.5760","article-title":"Human CD25+ regulatory T cells maintain immune tolerance to nickel in healthy, nonallergic individuals","volume":"171","author":"Cavani","year":"2003","journal-title":"J. Immunol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"e1096","DOI":"10.1002\/cti2.1096","article-title":"Circulating gluten-specific, but not CMV-specific, CD39+ regulatory T cells have an oligoclonal TCR repertoire","volume":"9","author":"Cook","year":"2020","journal-title":"Clin. Transl. Immunol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/ajd.12087","article-title":"Allergic contact dermatitis to chlorhexidine","volume":"54","author":"Toholka","year":"2013","journal-title":"Australas J. Dermatol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1002\/eji.1830220335","article-title":"Antigen contact sites in class I major histocompatibility complex-restricted, trinitrophenyl-specific T cell receptors","volume":"22","author":"Weltzien","year":"1992","journal-title":"Eur. J. Immunol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.it.2016.08.010","article-title":"Present Yourself! By MHC Class I and MHC Class II Molecules","volume":"37","author":"Rock","year":"2016","journal-title":"Trends. Immunol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/s41577-022-00707-2","article-title":"A guide to antigen processing and presentation","volume":"22","author":"Pishesha","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.4049\/jimmunol.148.5.1445","article-title":"Synthetic peptides anchor T cell-specific TNP epitopes to MHC antigens","volume":"148","author":"Ortmann","year":"1992","journal-title":"J. Immunol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"22","DOI":"10.4049\/jimmunol.1502011","article-title":"Beryllium-Induced Hypersensitivity: Genetic Susceptibility and Neoantigen Generation","volume":"196","author":"Fontenot","year":"2016","journal-title":"J. Immunol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/eji.1830260202","article-title":"Alteration of a model antigen by Au(III) leads to T cell sensitization to cryptic peptides","volume":"26","author":"Griem","year":"1996","journal-title":"Eur. J. Immunol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.4049\/jimmunol.172.3.1926","article-title":"Metal-protein complex-mediated transport and delivery of Ni2+ to TCR\/MHC contact sites in nickel-specific human T cell activation","volume":"172","author":"Thierse","year":"2004","journal-title":"J. Immunol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1034\/j.1398-9995.2000.00107.x","article-title":"Immunologic mechanisms in hypersensitivity reactions to metal ions: An overview","volume":"55","author":"Budinger","year":"2000","journal-title":"Allergy"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/jid.2009.271","article-title":"Characterization of p-phenylenediamine-albumin binding sites and T-cell responses to hapten-modified protein","volume":"130","author":"Jenkinson","year":"2010","journal-title":"J. Investig. Dermatol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/sj.jid.5700581","article-title":"Investigation of mechanisms underlying the T-cell response to the hapten 2,4-dinitrochlorobenzene","volume":"127","author":"Pickard","year":"2007","journal-title":"J. Investig. Dermatol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.tox.2004.12.015","article-title":"T cell receptor (TCR) interaction with haptens: Metal ions as non-classical haptens","volume":"209","author":"Thierse","year":"2005","journal-title":"Toxicology"},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Oakes, T., Popple, A.L., Williams, J., Best, K., Heather, J.M., Ismail, M., Maxwell, G., Gellatly, N., Dearman, R.J., and Kimber, I. (2017). The T Cell Response to the Contact Sensitizer Paraphenylenediamine Is Characterized by a Polyclonal Diverse Repertoire of Antigen-Specific Receptors. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.00162"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/cod.13246","article-title":"T lymphocyte phenotype of contact-allergic patients: Experience with nickel and p-phenylenediamine","volume":"81","author":"Wicks","year":"2019","journal-title":"Contact Dermat."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1021\/tx700040s","article-title":"Mechanistic studies on the lysine-induced N-formylation of 2,5-dimethyl-p-benzoquinonediimine","volume":"20","author":"Eilstein","year":"2007","journal-title":"Chem. Res. Toxicol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1093\/toxsci\/kfx265","article-title":"Determination of Protein Haptenation by Chemical Sensitizers Within the Complexity of the Human Skin Proteome","volume":"162","author":"Parkinson","year":"2018","journal-title":"Toxicol. Sci."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1016\/j.nano.2015.02.001","article-title":"Encapsulation of hydrophobic allergens into nanoparticles improves the in vitro immunological diagnosis of allergic contact dermatitis","volume":"11","author":"Cortial","year":"2015","journal-title":"Nanomedicine"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"4493","DOI":"10.2147\/IJN.S134630","article-title":"Nanoparticle-allergen complexes for allergen immunotherapy","volume":"12","author":"Colombo","year":"2017","journal-title":"Int. J. Nanomed."},{"key":"ref_162","doi-asserted-by":"crossref","unstructured":"Pateiro, M., Gomez, B., Munekata, P.E.S., Barba, F.J., Putnik, P., Kovacevic, D.B., and Lorenzo, J.M. (2021). Nanoencapsulation of Promising Bioactive Compounds to Improve Their Absorption, Stability, Functionality and the Appearance of the Final Food Products. Molecules, 26.","DOI":"10.3390\/molecules26061547"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/cyto.b.20485","article-title":"Considerations for the control of background fluorescence in clinical flow cytometry","volume":"76","author":"Hulspas","year":"2009","journal-title":"Cytom. B Clin. Cytom."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.5114\/aoms\/131088","article-title":"Flow cytometric characterization of cell surface markers to differentiate between fibroblasts and mesenchymal stem cells of different origin","volume":"19","author":"Sober","year":"2023","journal-title":"Arch. Med. Sci."},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"Robinson, J.P., Ostafe, R., Iyengar, S.N., Rajwa, B., and Fischer, R. (2023). Flow Cytometry: The Next Revolution. Cells, 12.","DOI":"10.3390\/cells12141875"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1007\/s10616-012-9530-6","article-title":"Considerations regarding use of solvents in in vitro cell based assays","volume":"65","author":"Timm","year":"2013","journal-title":"Cytotechnology"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.jim.2018.09.004","article-title":"CD4+ T cell activation, function, and metabolism are inhibited by low concentrations of DMSO","volume":"463","author":"Holthaus","year":"2018","journal-title":"J. Immunol. Methods"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1159\/000074905","article-title":"Cytokine production, lymphocyte proliferation and T-cell receptor Vbeta expression in primary peripheral blood mononuclear cell cultures from nickel-allergic individuals","volume":"132","author":"Cederbrant","year":"2003","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"511","DOI":"10.2340\/0001555561511515","article-title":"Lymphocyte transformation test in patients with nickel sensitivity: An aid to diagnosis","volume":"61","author":"Marcusson","year":"1981","journal-title":"Acta. Derm. Venereol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/j.cell.2016.09.050","article-title":"Regulatory T Cell Specificity Directs Tolerance versus Allergy against Aeroantigens in Humans","volume":"167","author":"Bacher","year":"2016","journal-title":"Cell"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1067\/mai.2002.123872","article-title":"Delayed-type hypersensitivity reaction to paraphenylenediamine is mediated by 2 different pathways of antigen recognition by specific alphabeta human T-cell clones","volume":"109","author":"Sieben","year":"2002","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1111\/cod.14170","article-title":"Patch test results with the European baseline series, 2019\/20-Joint European results of the ESSCA and the EBS working groups of the ESCD, and the GEIDAC","volume":"87","author":"Uter","year":"2022","journal-title":"Contact Dermat."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"82","DOI":"10.5414\/ALX2483E","article-title":"Patch testing in occupational dermatology: Practical aspects in relation to the conditions in Germany","volume":"8","author":"Brans","year":"2024","journal-title":"Allergol. Select."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/cod.14569","article-title":"Less efficient skin penetration of the metal allergen Pd2+ compared to Ni2+ and Co2+ from patch test preparations","volume":"91","author":"Simon","year":"2024","journal-title":"Contact Dermat."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1111\/cod.12271","article-title":"Patch test study of 90 patients with tattoo reactions: Negative outcome of allergy patch test to baseline batteries and culprit inks suggests allergen(s) are generated in the skin through haptenization","volume":"71","author":"Serup","year":"2014","journal-title":"Contact Dermat."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1111\/cod.12751","article-title":"Evaluation of lymphocyte transformation tests as compared with patch tests in nickel allergy diagnosis","volume":"76","author":"Stander","year":"2017","journal-title":"Contact Dermat."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1007\/978-1-4419-6451-9_8","article-title":"Longevity of T-cell memory following acute viral infection","volume":"684","author":"Walker","year":"2010","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1038\/nm917","article-title":"Duration of antiviral immunity after smallpox vaccination","volume":"9","author":"Hammarlund","year":"2003","journal-title":"Nat. Med."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"e63502","DOI":"10.7554\/eLife.63502","article-title":"Longitudinal high-throughput TCR repertoire profiling reveals the dynamics of T-cell memory formation after mild COVID-19 infection","volume":"10","author":"Minervina","year":"2021","journal-title":"eLife"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"4431","DOI":"10.4049\/jimmunol.176.7.4431","article-title":"The vast majority of CLA+ T cells are resident in normal skin","volume":"176","author":"Clark","year":"2006","journal-title":"J. Immunol."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1007\/BF03362255","article-title":"In-vitro-Allergiediagnostik\u2014Leitlinie der Deutschen Gesellschaft f\u00fcr Allergologie und klinische Immunologie (DGAKI) unter Beteiligung des \u00c4rzteverbandes Deutscher Allergologen (\u00c4DA), der Gesellschaft f\u00fcr P\u00e4diatrische Allergologie und Umweltmedizin (GPA) und der Deutschen Dermatologische Gesellschaft (DDG)","volume":"19","author":"Renz","year":"2010","journal-title":"Allergo J. Int."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"279ra39","DOI":"10.1126\/scitranslmed.3010302","article-title":"Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells","volume":"7","author":"Watanabe","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"3981","DOI":"10.4049\/jimmunol.1701728","article-title":"Simultaneous Presence of Non- and Highly Mutated Keyhole Limpet Hemocyanin (KLH)-Specific Plasmablasts Early after Primary KLH Immunization Suggests Cross-Reactive Memory B Cell Activation","volume":"200","author":"Giesecke","year":"2018","journal-title":"J. Immunol."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/s41577-023-00835-3","article-title":"Can we predict T cell specificity with digital biology and machine learning?","volume":"23","author":"Hudson","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_185","first-page":"9008E","article-title":"Proposal for a qualification system for New Approach Methodologies (NAMs) in the food and feed sector: Example of implementation for nanomaterial risk assessment","volume":"21","author":"Haase","year":"2024","journal-title":"EFSA Support. Publ."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"e2006027","DOI":"10.1002\/smll.202006027","article-title":"Understanding the Development, Standardization, and Validation Process of Alternative In Vitro Test Methods for Regulatory Approval from a Researcher Perspective","volume":"17","author":"Bas","year":"2021","journal-title":"Small"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1177\/026119290403200503","article-title":"A modular approach to the ECVAM principles on test validity","volume":"32","author":"Hartung","year":"2004","journal-title":"Altern. Lab. Anim."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/j.tiv.2010.03.016","article-title":"Optimization of chemically defined cell culture media--replacing fetal bovine serum in mammalian in vitro methods","volume":"24","author":"Brunner","year":"2010","journal-title":"Toxicol. Vitr."},{"key":"ref_189","doi-asserted-by":"crossref","unstructured":"Duarte, A.C., Costa, E.C., Filipe, H.A.L., Saraiva, S.M., Jacinto, T., Miguel, S.P., Ribeiro, M.P., and Coutinho, P. (2023). Animal-derived products in science and current alternatives. Biomater. Adv., 151.","DOI":"10.1016\/j.bioadv.2023.213428"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1007\/s00204-023-03656-4","article-title":"Use of human predictive patch test (HPPT) data for the classification of skin sensitization hazard and potency","volume":"98","author":"Herzler","year":"2024","journal-title":"Arch. Toxicol."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"105244","DOI":"10.1016\/j.yrtph.2022.105244","article-title":"Reference Chemical Potency List (RCPL): A new tool for evaluating the accuracy of skin sensitisation potency measurements by New Approach Methodologies (NAMs)","volume":"134","author":"Irizar","year":"2022","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"105597","DOI":"10.1016\/j.yrtph.2024.105597","article-title":"GARDskin dose-response assay and its application in conducting Quantitative Risk Assessment (QRA) for fragrance materials using a Next Generation Risk Assessment (NGRA) framework","volume":"149","author":"Donthamsetty","year":"2024","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"6794","DOI":"10.4049\/jimmunol.167.12.6794","article-title":"Tolerance to nickel: Oral nickel administration induces a high frequency of anergic T cells with persistent suppressor activity","volume":"167","author":"Artik","year":"2001","journal-title":"J. Immunol."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.tox.2004.12.021","article-title":"Breaking tolerance to nickel","volume":"209","author":"Cavani","year":"2005","journal-title":"Toxicology"}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/12\/11\/802\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:27:13Z","timestamp":1760113633000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/12\/11\/802"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,6]]},"references-count":194,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["toxics12110802"],"URL":"https:\/\/doi.org\/10.3390\/toxics12110802","relation":{},"ISSN":["2305-6304"],"issn-type":[{"value":"2305-6304","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,6]]}}}