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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Morel
E
E
Research Unit, Hospital Universitario La Paz, Madrid, Spain.
Bellón
T
T
D000658:Amoxicillin / Q000276:immunology / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D006680:HLA Antigens / Q000276:immunology*; D015235:HLA-B Antigens / Q000276:immunology*; D015796:HLA-B27 Antigen; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D015703:Antigens, CD; D006680:HLA Antigens; D015235:HLA-B Antigens; C464936:HLA-B*27:05 antigen; D015796:HLA-B27 Antigen; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D018796:Immunoconjugates; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D011971:Receptors, Immunologic; D000658:Amoxicillin; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6