Molinero Luciana Lorena, Domaica Carolina Inés, Fuertes Mercedes Beatriz, Girart María Victoria, Rossi Lucas Ezequiel, Zwirner Norberto Walter
Laboratorio de Immunogenética, Hospital de Clínicas José de San Martín and Departamento de Microbiología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
Hum Immunol. 2006 Mar;67(3):170-82. doi: 10.1016/j.humimm.2006.02.010. Epub 2006 Mar 31.
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.
MICA是一种受应激调节的分子，可被自然杀伤细胞（NK）激活受体NKG2D识别。此前，我们证明MICA在活化的T细胞上被诱导表达，但有丝分裂原细胞因子对其的调控及其生物学后果仍未得到探索。在此，我们发现，通过蛋白质印迹法评估，白细胞介素-2（IL-2）、白细胞介素-4（IL-4）和白细胞介素-15（IL-15）可诱导外周血单核细胞（PBMC）中的T淋巴细胞表达MICA，而肿瘤坏死因子-α（TNF-α）或干扰素-α（IFN-α）则无此作用。IL-2的作用涉及Jak3/信号转导子和转录激活子5（STAT5）、p38丝裂原活化蛋白激酶（MAPK）、p70(56)激酶、淋巴细胞特异性蛋白酪氨酸激酶（Lck）/Fyn激酶以及核因子κB（NF-κB）。在Th1和Th2细胞中也观察到了MICA的表达。然而，未检测到其表面表达。通过蛋白质印迹法评估，用佛波醇-12-肉豆蔻酸酯-13-乙酸酯（PMA）和离子霉素刺激的PBMC中的T淋巴细胞以及分离的CD4⁺ T淋巴细胞也可诱导MICA表达，但细胞表面仅表达低水平的MICA。活化而非静息的CD4⁺ T淋巴细胞会被IL-15或IL-2刺激的NK细胞裂解，当I类人白细胞抗原（HLA）分子被阻断时，敏感性增加。此外，细胞因子刺激的NK细胞在与活化的CD4⁺ T淋巴细胞共培养后会产生更多的干扰素-γ（IFN-γ）。然而，MICA在这些反应中的参与（如果有）微乎其微。共聚焦显微镜显示，MICA大多保留在活化的CD4⁺ T细胞内。我们的结果表明，活化的CD4⁺ T淋巴细胞上MICA的低表面表达可能是一种保护机制，可在炎症、病毒感染或肿瘤微环境中保护它们免受NK细胞的攻击，在这些微环境中，NK细胞和活化的CD4⁺ T细胞会被募集。
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