HLA Class-II‒Restricted CD8⁺ T Cells Contribute to the Promiscuous Immune Response in Dapsone-Hypersensitive...

Area of Science:

• Immunology
• Pharmacogenomics
• T-cell biology

Background:

• HLA-B*13:01 is linked to dapsone (DDS)-induced hypersensitivity.
• Both DDS and its metabolite, nitroso dapsone (DDS-NO), activate CD4+ and CD8+ T cells.
• The precise role of HLA association in disease pathogenesis requires further elucidation.

Purpose of the Study:

• To investigate the role of HLA in dapsone hypersensitivity by generating and characterizing DDS- and DDS-NO-specific CD8+ T-cell clones (TCCs).
• To assess the phenotype, function, HLA allele restriction, and cytotoxic activity of these TCCs.

Main Methods:

• Generation of DDS- and DDS-NO-specific CD8+ TCCs from hypersensitive patients with HLA-B*13:01.
• Assessment of TCC proliferation, effector molecule secretion, HLA restriction, and target cell killing.
• Analysis of TCC surface markers (CD45RO, CD28, PD-1, CTLA-4) and TCR sequences.
• Investigation of HLA class I and class II restriction pathways, including hapten pathway activation.

Main Results:

• DDS- and DDS-NO-responsive CD8+ TCCs demonstrated HLA class I restriction, interacting with multiple HLA-B alleles.
• Certain DDS-NO-responsive CD8+ TCCs showed HLA class II restriction (binding to HLA-DQB1*05:01) and exhibited hybrid CD4-CD8 features.
• These HLA class II-restricted TCCs, despite having identical TCR amino acid sequences, showed reduced target cell lysis compared to HLA class I-restricted TCCs.
• Both HLA class I and class II restricted TCCs secreted similar effector molecules.

Conclusions:

• Dapsone and its metabolite DDS-NO engage various HLA molecules to activate CD8+ T cells.
• HLA class II-restricted CD8+ T cells with hybrid CD4-CD8 phenotypes contribute to the diverse immune response in dapsone hypersensitivity.
• These findings highlight the complex pharmacogenetic mechanisms underlying drug-induced hypersensitivity reactions.