Browsing by Author "David J. MacEwan"

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    HLA Class-II‒Restricted CD8+ T Cells Contribute to the Promiscuous Immune Response in Dapsone-Hypersensitive Patients
    (2021-10-01) Qing Zhao; Mubarak Almutairi; Arun Tailor; Adam Lister; Nicolas Harper; James Line; Xiaoli Meng; Jirawat Pratoomwun; Kanoot Jaruthamsophon; Chonlaphat Sukasem; Yonghu Sun; Lele Sun; Monday O. Ogese; David J. MacEwan; Munir Pirmohamed; Jianjun Liu; David A. Ostrov; Hong Liu; Furen Zhang; Dean J. Naisbitt; Ramathibodi Hospital; A-Star, Genome Institute of Singapore; University of Liverpool; Faculty of Medicine Ramathibodi Hospital, Mahidol University; Huachiew Chalermprakiet University; University of Florida College of Medicine; Shandong Provincial Hospital
    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.