Intracellular Expression of MICA in Activated CD4 T Lymphocytes and Protection from NK Cell-Mediated MICA-Dependent Cytotoxicity

• Published in: Human Immunology Vol. 67; no. 3; pp. 170 - 182
• Main Authors: Molinero, Luciana Lorena, Domaica, Carolina Inés, Fuertes, Mercedes Beatriz, Girart, Marı́a Victoria, Rossi, Lucas Ezequiel, Zwirner, Norberto Walter
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2006
• Subjects: CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; Cell Survival; Cytokines - metabolism; Cytotoxicity, Immunologic; Histocompatibility Antigens Class I - biosynthesis; Humans; Ionomycin - pharmacology; Killer Cells, Natural - physiology; Lymphocyte Activation; MHC; MICA; Microscopy, Confocal; NK cells; Protein Kinases - metabolism; T lymphocytes; Tetradecanoylphorbol Acetate - analogs & derivatives; Tetradecanoylphorbol Acetate - pharmacology; Th1 Cells - drug effects; Th1 Cells - metabolism; Th2 Cells - drug effects; Th2 Cells - metabolism; T lymphocytes; MHC; NK cells; MICA
• ISSN: 0198-8859; 1879-1166; 1365-2567
• DOI: 10.1016/j.humimm.2006.02.010

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-α or IFN-α 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-κB. 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-γ 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.