title: Intracellular expression of MICA in activated CD4 T lymphocytes and protection from NK cell-mediated MICA-dependent cytotoxicity.
abstract: MICA is a stress-regulated molecule recognized by the NK cell-activating receptor NKG2D. Previously, we demonstrated that MICA is induced on activated T cells but regulation by mitogenic cytokines and its biological consequences remain unexplored. Here, we show that IL-2, IL-4, and IL-15 but not TNF-alpha or IFN-alpha induced MICA expression in T lymphocytes present in peripheral blood mononuclear cells (PBMCs), as assessed by Western blot. IL-2 effect involved Jak3/STAT5, p38 MAPK, p70(56) kinase, Lck/fyn kinases, and NF-kappaB. MICA expression was also observed in Th1 and Th2 cells. However, surface expression was not detected. T lymphocytes present in PBMCs and isolated CD4+ T lymphocytes stimulated with phorbol-12-myristate-13-acetate and ionomycin also induced MICA expression as assessed by Western blot, but only low levels were expressed at the cell surface. Activated but not resting CD4+ T lymphocytes were lysed by IL-15- or IL-2-stimulated NK cells, and susceptibility was increased when HLA class I molecules were blocked. Also, cytokine-stimulated NK cells produced more IFN-gamma after culture with activated CD4+ T lymphocytes. However, the participation of MICA in these responses, if any, was marginal. Confocal microscopy revealed that MICA is retained mostly inside activated CD4+ T cells. Our results suggest that low surface expression of MICA on activated CD4+ T lymphocytes might be a safeguard mechanism to protect them from NK cells in an inflammatory, virus-infected, or tumor microenvironment, where NK and activated CD4+ T cells are recruited.
authors.affiliation: Laboratorio de Immunogenética, Hospital de Clínicas José de San Martín and Departamento de Microbiología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Luciana Lorena
authors.initials: LL
authors.lastname: Molinero
authors.forename: Carolina Inés
authors.initials: CI
authors.lastname: Domaica
authors.forename: Mercedes Beatriz
authors.initials: MB
authors.lastname: Fuertes
authors.forename: María Victoria
authors.initials: MV
authors.lastname: Girart
authors.forename: Lucas Ezequiel
authors.initials: LE
authors.lastname: Rossi
authors.forename: Norberto Walter
authors.initials: NW
authors.lastname: Zwirner
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000502:physiology*; D008213:Lymphocyte Activation; D018613:Microscopy, Confocal; D011494:Protein Kinases / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D016207:Cytokines; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; D015759:Ionomycin; C016658:phorbolol myristate acetate; D011494:Protein Kinases; D013755:Tetradecanoylphorbol Acetate