HLA Class II-restricted CD8+ T cells contribute to the promiscuous immune response in dapsone hypersensitive patients.

Abstract 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 (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 (TCC) were generated from hypersensitive patients expressing HLA-B*13:01 and assessed for phenotype and function, HLA-allele restriction, and killing of target cells. CD8+ TCC were stimulated to proliferate and secrete effector molecules when exposed to DDS and/or DDS-NO. DDS-responsive and several DDS-NO-responsive TCC 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+ TCC was inhibited with HLA-class-II block, with DDS-NO binding to HLA-DQB1*05:01. These TCC were of different origin, but expressed TCRs displaying the same amino acid sequences. They were activated via a hapten pathway, displayed a CD45RO, CD28, PD-1 and CTLA-4 surface molecules, secreted the same panel of effector molecules as HLA class-I-restricted TCC, 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+ TCC, with HLA class-II-restricted CD8+ TCC that display hybrid CD4/CD8 features also contributing to the promiscuous immune response that develops in patients.