Amoxicillin conjugates to HLA class I molecules and interferes with signalling through the ILT2/LIR-1/CD85j inhibitory receptor.

Abstract

Drugs behave as haptens and are recognized by specific T-cell receptors in the context of major histocompatibility complex (MHC) molecules in allergic subjects. Natural killer cell receptors (NKRs) are MHC class I-specific receptors that modulate the threshold of activation of immunocompetent cells. Amongst them, ILT2/LIR-1/CD85j is an inhibitory NKR widely distributed in several cell lineages and with a broad spectrum of recognition of human leucocyte antigen (HLA) class I ligands. We have evaluated, at the biochemical and cellular level, the ability of amoxicillin (AX) conjugate to HLA class I molecules and to interfere with the inhibitory signal delivered by the HLA class I receptor ILT2/LIR-1/CD85j. We have detected AX bound to cell membrane proteins and in particular to HLA class I molecules. Preincubation with AX rendered target cells susceptible to NK cell-mediated lysis. In conjugation experiments, target cell-bound AX hampered tyrosine phosphorylation of ILT2/LIR-1/CD85j upon ligand recognition and the subsequent recruitment of SHP-1 phosphatase. Conjugation of AX to HLA class I molecules may mask HLA recognition by inhibitory receptors and attenuate the negative signal delivered by SHP-1 phosphatase, thus lowering the threshold of activation of effector cells.