HLA Class-II. Restricted CD8<SUP>+</SUP> T Cells Contribute to the Promiscuous Immune Response in Dapsone-Hypersensitive Patients

Zhao, Qing, Almutairi, Mubarak, Tailor, Arun, Lister, Adam, Harper, Nicolas, Line, James ORCID: 0000-0003-3568-8928, Meng, Xiaoli ORCID: 0000-0002-7774-2075, Pratoomwun, Jirawat, Jaruthamsophon, Kanoot ORCID: 0000-0003-1563-0024, Sukasem, Chonlaphat
et al (show 10 more authors) (2021) HLA Class-II. Restricted CD8<SUP>+</SUP> T Cells Contribute to the Promiscuous Immune Response in Dapsone-Hypersensitive Patients. JOURNAL OF INVESTIGATIVE DERMATOLOGY, 141 (10). 2412-+.

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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.

Item Type: Article
Uncontrolled Keywords: CD8-Positive T-Lymphocytes, Humans, Dapsone, Histocompatibility Antigens Class II, Lymphocyte Activation, Cytotoxicity, Immunologic, Alleles, Adult, Female, Male, Young Adult, Drug Hypersensitivity Syndrome
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 13 Jul 2021 10:25
Last Modified: 16 Oct 2023 18:01
DOI: 10.1016/j.jid.2021.03.014
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3128545