Abstract
Allergic contact dermatitis (ACD) is the result of an exaggerated immune reaction to haptens mediated by skin-homing T cells, but the effector mechanisms responsible for the tissue damage are poorly understood. Here we studied the capacity of distinct subsets of hapten-specific T cells to induce apoptosis in autologous keratinocytes. Skin- and blood-derived nickel-specific CD8+ T cytotoxic 1 (Tc1) and Tc2 clones as well as CD4+ Th1 and Th2 expressed the cutaneous lymphocyte-associated Ag and exhibited strong MHC-restricted cytotoxicity against nickel-coupled B lymphoblasts, as detected by the [3H]TdR release assay. Both Tc1 and Tc2 clones, but not CD4+ T cells, displayed a significant cytotoxic activity against resting nickel-modified keratinocytes. Following IFN-gamma treatment, keratinocytes expressed MHC class II and ICAM-1 and became susceptible to Th1-mediated, but not Th2-mediated, cytotoxicity. The molecules of the two major cytotoxic pathways, Fas ligand (FasL) and perforin, were expressed by Tc1, Tc2, and Th1 cells, whereas Th2 cells expressed only FasL. Experiments performed in the presence of specific inhibitors of the perforin (concanamycin A) and FasL (brefeldin A) pathway indicated that perforin-mediated killing dominated in Tc1 and Tc2, and FasL-mediated cytotoxicity prevailed in Th2 clones, with a more heterogeneous behavior in the case of Th1 cells. Finally, perforin mRNA was expressed in ACD lesional skin, as assessed by RT-PCR analysis. In aggregate, our results indicate that keratinocytes can be target of multiple hapten-specific CTL responses, that may have distinct roles in the epidermal injury during ACD.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / enzymology
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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Cell Line
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Cell Line, Transformed
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Clone Cells
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Cytokines / biosynthesis
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Cytoplasmic Granules / enzymology
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Cytoplasmic Granules / immunology
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Cytotoxicity Tests, Immunologic
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Cytotoxicity, Immunologic / immunology*
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Dermatitis, Contact / immunology
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Dermatitis, Contact / metabolism
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Down-Regulation / immunology
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Epitopes, T-Lymphocyte / immunology*
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Exocytosis / immunology
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Fas Ligand Protein
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Histocompatibility Antigens Class I / biosynthesis
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Histocompatibility Antigens Class II / biosynthesis
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Humans
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Immunophenotyping
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Intercellular Adhesion Molecule-1 / biosynthesis
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Keratinocytes / immunology*
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Keratinocytes / metabolism
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Ligands
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology
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Nickel / immunology*
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Perforin
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Pore Forming Cytotoxic Proteins
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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RNA, Messenger / biosynthesis
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Serine Endopeptidases / physiology
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T-Lymphocyte Subsets / enzymology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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T-Lymphocytes, Cytotoxic / enzymology
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T-Lymphocytes, Cytotoxic / immunology*
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T-Lymphocytes, Cytotoxic / metabolism
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Up-Regulation / immunology
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fas Receptor / biosynthesis
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fas Receptor / physiology
Substances
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Cytokines
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Epitopes, T-Lymphocyte
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FASLG protein, human
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Fas Ligand Protein
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Histocompatibility Antigens Class I
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Histocompatibility Antigens Class II
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Ligands
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Membrane Glycoproteins
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Pore Forming Cytotoxic Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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fas Receptor
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Perforin
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Intercellular Adhesion Molecule-1
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Nickel
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Serine Endopeptidases