Journal
TOXICOLOGICAL SCIENCES
Volume 180, Issue 1, Pages 136-147Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfaa184
Keywords
HLA; peptidome; DNCB; keratinocyte; HaCaT
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Funding
- SEAC, Unilever plc [CH2012-0929]
- BBSRC [BB/M012387/1] Funding Source: UKRI
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Skin sensitization following haptenation involves CTL recognition of HLA molecules, possibly through direct stimulation by haptenated peptides. Proteomic analysis after exposure to 2,4-dinitrochlorobenzene revealed cysteine haptenated peptides presented by cultured keratinocytes, supporting the mechanism of CTL stimulation by haptenated peptides.
Skin sensitization following the covalent modification of proteins by low molecular weight chemicals (haptenation) is mediated by cytotoxic T lymphocyte (CTL) recognition of human leukocyte antigen (HLA) molecules presented on the surface of almost all nucleated cells. There exist 3 nonmutually exclusive hypotheses for how haptens mediate CTL recognition: direct stimulation by haptenated peptides, hapten modification of HLA leading to an altered HLA-peptide repertoire, or a hapten altered proteome leading to an altered HLA-peptide repertoire. To shed light on the mechanism underpinning skin sensitization, we set out to utilize proteomic analysis of keratinocyte presented antigens following exposure to 2,4-dinitrochlorobenzene (DNCB). We show that the following DNCB exposure, cultured keratinocytes present cysteine haptenated (dinitrophenylated) peptides in multiple HLA molecules. In addition, we find that one of the DNCB modified peptides derives from the active site of cytosolic glutathione-S transferase-omega. These results support the current view that a key mechanism of skin sensitization is stimulation of CTLs by haptenated peptides. Data are available via ProteomeXchange with identifier PXD021373.
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