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.
Abstract
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 |
| Open Access URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC76144... |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3169740 |
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