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HLA Class-II‒Restricted CD8+ T Cells Contribute to the Promiscuous Immune Response in Dapsone-Hypersensitive Patients

  • Qing Zhao
    Affiliations
    MRC Centre for Drug Safety Science, Department of Pharmacology & Therapeutics, The University of Liverpool, Liverpool, United Kingdom

    Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
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  • Mubarak Almutairi
    Affiliations
    MRC Centre for Drug Safety Science, Department of Pharmacology & Therapeutics, The University of Liverpool, Liverpool, United Kingdom
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  • Arun Tailor
    Affiliations
    MRC Centre for Drug Safety Science, Department of Pharmacology & Therapeutics, The University of Liverpool, Liverpool, United Kingdom
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  • Adam Lister
    Affiliations
    MRC Centre for Drug Safety Science, Department of Pharmacology & Therapeutics, The University of Liverpool, Liverpool, United Kingdom
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  • Nicolas Harper
    Affiliations
    MRC Centre for Drug Safety Science, Department of Pharmacology & Therapeutics, The University of Liverpool, Liverpool, United Kingdom
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  • James Line
    Affiliations
    MRC Centre for Drug Safety Science, Department of Pharmacology & Therapeutics, The University of Liverpool, Liverpool, United Kingdom
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  • Xiaoli Meng
    Affiliations
    MRC Centre for Drug Safety Science, Department of Pharmacology & Therapeutics, The University of Liverpool, Liverpool, United Kingdom
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  • Jirawat Pratoomwun
    Affiliations
    Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

    Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Centre (SDMC), Ramathibodi Hospital, Bangkok, Thailand

    Faculty of Medical Technology, Huachiew Chalermprakiet University, Samut Prakan, Thailand
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  • Kanoot Jaruthamsophon
    Affiliations
    MRC Centre for Drug Safety Science, Department of Pharmacology & Therapeutics, The University of Liverpool, Liverpool, United Kingdom

    Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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  • Chonlaphat Sukasem
    Affiliations
    Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

    Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Centre (SDMC), Ramathibodi Hospital, Bangkok, Thailand
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  • Yonghu Sun
    Affiliations
    Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
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  • Lele Sun
    Affiliations
    Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
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  • Monday O. Ogese
    Affiliations
    MRC Centre for Drug Safety Science, Department of Pharmacology & Therapeutics, The University of Liverpool, Liverpool, United Kingdom
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  • David J. MacEwan
    Affiliations
    MRC Centre for Drug Safety Science, Department of Pharmacology & Therapeutics, The University of Liverpool, Liverpool, United Kingdom
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  • Munir Pirmohamed
    Affiliations
    MRC Centre for Drug Safety Science, Department of Pharmacology & Therapeutics, The University of Liverpool, Liverpool, United Kingdom
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  • Jianjun Liu
    Affiliations
    Human Genetics, Genome Institute of Singapore, A∗STAR, Singapore
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  • David A. Ostrov
    Affiliations
    Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
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  • Hong Liu
    Affiliations
    Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
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  • Furen Zhang
    Correspondence
    Correspondence: Furen Zhang, Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, 27397 Jingshi Road, Jinan, Shandong Province, China.
    Affiliations
    Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
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  • Dean J. Naisbitt
    Affiliations
    MRC Centre for Drug Safety Science, Department of Pharmacology & Therapeutics, The University of Liverpool, Liverpool, United Kingdom
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Published:March 30, 2021DOI:https://doi.org/10.1016/j.jid.2021.03.014
      HLA-B∗13:01 is associated with dapsone (DDS)-induced hypersensitivity, and it has been shown that CD4+ and CD8+ T cells are activated by DDS and its nitroso metabolite (nitroso dapsone [DDS-NO]). However, there is a need to define the importance of the HLA association in the disease pathogenesis. Thus, DDS- and DDS-NO‒specific CD8+ T-cell clones (TCCs) were generated from hypersensitive patients expressing HLA-B∗13:01 and were assessed for phenotype and function, HLA allele restriction, and killing of target cells. CD8+ TCCs were stimulated to proliferate and secrete effector molecules when exposed to DDS and/or DDS-NO. DDS-responsive and several DDS-NO‒responsive TCCs expressing a variety of TCR sequences displayed HLA class-I restriction, with the drug (metabolite) interacting with multiple HLA-B alleles. However, activation of certain DDS-NO‒responsive CD8+ TCCs was inhibited with HLA class-II block, with DDS-NO binding to HLA-DQB1∗05:01. These TCCs were of different origin but expressed TCRs displaying the same amino acid sequences. They were activated through a hapten pathway; displayed CD45RO, CD28, PD-1, and CTLA-4 surface molecules; secreted the same panel of effector molecules as HLA class-I‒restricted TCCs; but displayed a lower capacity to lyse target cells. To conclude, DDS and DDS-NO interact with a number of HLA molecules to activate CD8+ TCCs, with HLA class-II‒restricted CD8+ TCCs that display hybrid CD4‒CD8 features also contributing to the promiscuous immune response that develops in patients.

      Graphical abstract

      Abbreviations:

      51Cr (chromium-51), APC (antigen-presenting cell), DDS (dapsone), DDS-NO (nitroso dapsone), EBV (Epstein‒Barr virus), PE (phycoerythrin), TCC (T-cell clone)
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      Supplementary Reference

        • Alzahrani A.
        • Ogese M.
        • Meng X.
        • Waddington J.C.
        • Tailor A.
        • Farrell J.
        • et al.
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