title: NK cells and gamma delta+ T cells are phenotypically and functionally defective due to preferential apoptosis in patients with atopic dermatitis.
abstract: Innate immune cells mediate a first line of defense against pathogens and determine the nature of subsequent acquired immune responses, mainly by producing profound amounts of cytokines. Given these diverse tasks, it is predictable that defective NK and gammadelta(+) T cell responses could be the underlying mechanism for the immunological alterations observed in atopic dermatitis (AD). Indeed, the frequencies of circulating NK cells and gammadelta(+) T cells were profoundly reduced in AD patients. They also displayed a defective ability to sustain TNF-alpha and IFN-gamma, but not IL-4, production after in vitro stimulation, and the defect was restricted to innate immune cells. Surprisingly, on the depletion of CD14(+) monocytes, this selective impairment of TNF-alpha and IFN-gamma production was restored to levels comparable to that observed in controls. Release of IL-10 from monocytes was not a major mechanism of the NK and gammadelta(+) T cell dysfunction. Apoptosis as revealed by annexin V binding, was preferentially observed in NK and gammadelta(+) T cells from AD patients when stimulated in the presence of monocytes, and depletion of monocytes significantly protected these cells from apoptotic cell death. Preferential apoptosis of NK cells by activated monocytes in AD patients was cell-contact-dependent. These results indicate that, once NK and gammadelta(+) T cells in AD patients are in immediate contact with activated monocytes, these cells are specifically targeted for apoptosis, leading to the reduced type 1 cytokine production, thereby directing subsequent acquired immune responses toward a type-2 pattern and increasing susceptibility to infection.
authors.affiliation: Department of Dermatology, Kyorin University School of Medicine, Tokyo, Japan. michic@kyorin-u.ac.jp
authors.forename: Michie
authors.initials: M
authors.lastname: Katsuta
authors.forename: Yukio
authors.initials: Y
authors.lastname: Takigawa
authors.forename: Momoko
authors.initials: M
authors.lastname: Kimishima
authors.forename: Miyuki
authors.initials: M
authors.lastname: Inaoka
authors.forename: Ryo
authors.initials: R
authors.lastname: Takahashi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shiohara
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003876:Dermatitis, Atopic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000276:immunology / Q000473:pathology; D008262:Macrophage Activation; D008297:Male; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000096:biosynthesis / Q000502:physiology*; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D016692:Receptors, Antigen, T-Cell, gamma-delta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma