Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 141, Issue 10, Pages 2412-+Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2021.03.014
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Funding
- China Scholarship Council [201806220227]
- Medical Research Council (MRC) [MR/R009635/1]
- Royal Society International Exchanges Cost Share (China) [IECyNSFCy170385]
- National Key Research and Development Program of China [2016YFE0201500]
- National Natural Science Foundation of China key program for international exchange and cooperation [81620108025]
- National Natural Science Foundation of China [81811530342, 81972946, 81903224]
- Academic promotion program of Shandong First Medical University [2019LJ002, 2019RC007]
- National Clinical Key Project of Dermatology and Venereology
- Shandong Provincial Advanced Taishan Scholar Construction Project
- Innovation Project of Shandong Academy of Medical Science
- MRC Centre for Drug Safety Science [G0700654]
- MRC [MR/L006758/1] Funding Source: UKRI
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HLA-B*13:01 is associated with dapsone-induced hypersensitivity. CD8+ T cell clones from hypersensitive patients were generated and showed that DDS and its metabolite DDS-NO activate T cells. DDS and DDS-NO interact with multiple HLA molecules, and certain CD8+ T cell clones with HLA class-II restriction also contribute to the immune response in patients.
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. DDSresponsive 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 HLADQB1*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 CD8thorn TCCs that display hybrid CD4-CD8 features also contributing to the promiscuous immune response that develops in patients.
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