Activation of Human CD8+ T Cells with Nitroso Dapsone-Modified HLA-B*13:01-Binding Peptides.

Almutairi, Mubarak, Lister, Adam ORCID: 0000-0003-4085-6367, Zhao, Qing, Line, James ORCID: 0000-0003-3568-8928, Adair, Kareena ORCID: 0000-0001-9884-2094, Tailor, Arun, Waddington, James ORCID: 0000-0003-2641-5055, Clarke, Elsie ORCID: 0000-0002-5913-0606, Gardner, Joshua ORCID: 0000-0002-4520-108X, Thomson, Paul ORCID: 0000-0001-5431-0459
et al (show 10 more authors) (2023) Activation of Human CD8+ T Cells with Nitroso Dapsone-Modified HLA-B*13:01-Binding Peptides. Journal of immunology (Baltimore, Md. : 1950), 210 (8). pp. 1031-1042.

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Previous studies have shown that cysteine-reactive drug metabolites bind covalently with protein to activate patient T cells. However, the nature of the antigenic determinants that interact with HLA and whether T cell stimulatory peptides contain the bound drug metabolite has not been defined. Because susceptibility to dapsone hypersensitivity is associated with the expression of HLA-B*13:01, we have designed and synthesized nitroso dapsone-modified, HLA-B*13:01 binding peptides and explored their immunogenicity using T cells from hypersensitive human patients. Cysteine-containing 9-mer peptides with high binding affinity to HLA-B*13:01 were designed (AQDCEAAAL [Pep1], AQDACEAAL [Pep2], and AQDAEACAL [Pep3]), and the cysteine residue was modified with nitroso dapsone. CD8+ T cell clones were generated and characterized in terms of phenotype, function, and cross-reactivity. Autologous APCs and C1R cells expressing HLA-B*13:01 were used to determine HLA restriction. Mass spectrometry confirmed that nitroso dapsone-peptides were modified at the appropriate site and were free of soluble dapsone and nitroso dapsone. APC HLA-B*13:01-restricted nitroso dapsone-modified Pep1- (n = 124) and Pep3-responsive (n = 48) CD8+ clones were generated. Clones proliferated and secreted effector molecules with graded concentrations of nitroso dapsone-modified Pep1 or Pep3. They also displayed reactivity against soluble nitroso dapsone, which forms adducts in situ, but not with the unmodified peptide or dapsone. Cross-reactivity was observed between nitroso dapsone-modified peptides with cysteine residues in different positions in the peptide sequence. These data characterize a drug metabolite hapten CD8+ T cell response in an HLA risk allele-restricted form of drug hypersensitivity and provide a framework for structural analysis of hapten HLA binding interactions.

Item Type: Article
Uncontrolled Keywords: CD8-Positive T-Lymphocytes, Humans, Drug Hypersensitivity, Cysteine, Dapsone, Peptides, HLA-B Antigens, Haptens
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Faculty of Health and Life Sciences > Tech, Infrastructure and Environmental Directorate
Depositing User: Symplectic Admin
Date Deposited: 19 Apr 2023 10:14
Last Modified: 29 Jun 2023 12:43
DOI: 10.4049/jimmunol.2200531
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