Qing ZhaoMubarak AlmutairiArun TailorAdam ListerNicolas HarperJames LineXiaoli MengJirawat PratoomwunKanoot JaruthamsophonChonlaphat SukasemYonghu SunLele SunMonday O. OgeseDavid J. MacEwanMunir PirmohamedJianjun LiuDavid A. OstrovHong LiuFuren ZhangDean J. NaisbittRamathibodi HospitalA-Star, Genome Institute of SingaporeUniversity of LiverpoolFaculty of Medicine Ramathibodi Hospital, Mahidol UniversityHuachiew Chalermprakiet UniversityUniversity of Florida College of MedicineShandong Provincial Hospital2022-08-042022-08-042021-10-01Journal of Investigative Dermatology. Vol.141, No.10 (2021), 2412-2425.e2152317470022202X2-s2.0-85105544537https://repository.li.mahidol.ac.th/handle/20.500.14594/76019HLA-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.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyMedicineArticleSCOPUS10.1016/j.jid.2021.03.014