CD94/NKG2C is a killer effector molecule in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis

• Published in: Journal of allergy and clinical immunology Vol. 125; no. 3; pp. 703 - 710.e8
• Main Authors: Morel, Esther, PhD, Escamochero, Salvador, BS, Cabañas, Rosario, MD, PhD, Díaz, Rosa, MD, PhD, Fiandor, Ana, MD, Bellón, Teresa, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.03.2010; Elsevier; Elsevier Limited
• Subjects: Allergy and Immunology; Biological and medical sciences; Blotting, Western; Bullous diseases of the skin; CD94/NKG2C; Cell Line; Cell Separation; Cloning; Cytotoxicity; Dermatology; drug allergy; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Histocompatibility Antigens Class I - biosynthesis; Histocompatibility Antigens Class I - immunology; HLA Antigens - biosynthesis; HLA Antigens - immunology; HLA-E; HLA-E Antigens; Humans; Immune system; Immunohistochemistry; Immunopathology; Keratinocytes - immunology; Lymphocyte Activation - immunology; Lymphocytes; Medical sciences; Mortality; Natural Killer T-Cells - immunology; NK Cell Lectin-Like Receptor Subfamily C - biosynthesis; NK Cell Lectin-Like Receptor Subfamily C - immunology; NK Cell Lectin-Like Receptor Subfamily D - biosynthesis; NK Cell Lectin-Like Receptor Subfamily D - immunology; NK-CTLs; Patients; Proteins; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Stevens-Johnson syndrome; Stevens-Johnson Syndrome - immunology; Stevens-Johnson Syndrome - metabolism; toxic epidermal necrolysis; Fluorescein isothiocyanate; Stevens-Johnson syndrome; Fas ligand; TCR; MPE; CD94/NKG2C; Killer immunoglobulin-like receptor; toxic epidermal necrolysis; T-cell receptor; Natural killer receptor; FITC; NK-CTLs; Maculopapular exanthema; Cytotoxic T lymphocyte; SJS; drug allergy; HLA-E; NKR; FasL; KIR; Natural killer; PE; Recombinant human; Blister fluid cell; rh; Phycoerythrin; CTL; TEN; NK; BFC; Bullous dermatosis; Human; Drug; Allergy; Immunopathology; HLA-System; Skin disease; Erythroderma; Stomatology; Cytotoxicity; Effector; Natural killer cell; Eye disease; Immunology; T-Lymphocyte; Lyell syndrome
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2009.10.030

Background Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are severe, bullous cutaneous diseases with uncertain pathogenesis, although cytotoxic T cells seem to be involved. Natural killer (NK)–like activity has been found in blister infiltrates. Cytotoxic T lymphocytes (CTLs) with NK-like activity (NK-CTLs) have been shown to express T-cell receptors restricted by the HLA-Ib molecule HLA-E. Alternatively, the HLA-E–specific activating receptor CD94/NKG2C can trigger T-cell receptor–independent cytotoxicity in CTLs. Objective Our aim was to test whether HLA-E expression sensitizes keratinocytes to killing by CTLs with NK-like activity and to explore the expression of activating receptors specific for HLA-E in blister cytotoxic lymphocytes. Methods We used flow cytometry and immunohistochemistry to analyze HLA-E expression in keratinocytes from affected skin in patients with SJS, TEN, and other less severe drug-induced exanthemas. The expression of CD94/NKG2C was analyzed by means of flow cytometry in PBMCs and blister cells from patients. PBMCs and blister cells were analyzed for their ability to kill HLA-E–expressing cells. Involvement of CD94/NKG2C in triggering degranulation of cytolytic cells was explored by means of CD107a mobilization assays and standard cytotoxicity chromium release assays. Results We found that keratinocytes from affected skin expressed HLA-E and that cell-surface HLA-E sensitizes keratinocytes to killing by CD94/NKG2C+ CTLs. Frequencies of CD94/NKG2C+ peripheral blood T and NK cells were increased in patients with SJS and TEN during the acute phase. Moreover, activated blister T and NK lymphocytes expressed CD94/NKG2C and were able to degranulate in response to HLA-E+ cells in an NKG2C-dependent manner. Conclusion CD94/NKG2C might be involved in triggering cytotoxic lymphocytes in patients with SJS and TEN.