Intracellular expression of MICA in activated CD4 T lymphocytes and protection from NK cell-mediated MICA-dependent cytotoxicity.
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.
Molinero
Luciana Lorena
LL
Laboratorio de Immunogenética, Hospital de Clínicas José de San Martín and Departamento de Microbiología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
Domaica
Carolina Inés
CI
Fuertes
Mercedes Beatriz
MB
Girart
María Victoria
MV
Rossi
Lucas Ezequiel
LE
Zwirner
Norberto Walter
NW
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
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