Article: article from journal or magazin.
HLA haplotype determines hapten or p-i T cell reactivity to flucloxacillin.
Journal of Immunology
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Drug-induced liver injury (DILI) is a main cause of drug withdrawal. A particularly interesting example is flucloxacillin (FLUX)-DILI, which is associated with the HLA-B*57:01 allele. At present, the mechanism of FLUX-DILI is not understood, but the HLA association suggests a role for activated T cells in the pathomechanism of liver damage. To understand the interaction among FLUX, HLA molecules, and T cells, we generated FLUX-reacting T cells from FLUX-naive HLA-B*57:01(+) and HLA-B*57:01(-) healthy donors and investigated the mechanism of T cell stimulation. We found that FLUX stimulates CD8(+) T cells in two distinct manners. On one hand, FLUX was stably presented on various HLA molecules, resistant to extensive washing and dependent on proteasomal processing, suggesting a hapten mechanism. On the other hand, in HLA-B*57:01(+) individuals, we observed a pharmacological interaction with immune receptors (p-i)-based T cell reactivity. FLUX was presented in a labile manner that was further characterized by independence of proteasomal processing and immediate T cell clone activation upon stimulation with FLUX in solution. This p-i-based T cell stimulation was restricted to the HLA-B*57:01 allele. We conclude that the presence of HLA-B*57:01 drives CD8(+) T cell responses to the penicillin-derivative FLUX toward nonhapten mechanism.
CD8-Positive T-Lymphocytes/immunology, Cells, Cultured, Drug-Induced Liver Injury/metabolism, Floxacillin/pharmacology, HLA-B Antigens/genetics, HLA-B Antigens/immunology, Haplotypes, Haptens, Humans, Liver/immunology, Liver/pathology, Lymphocyte Activation/immunology
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