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