NK cells and γδ+ T cells are phenotypically and functionally defective due to preferential apoptosis in patients with atopic dermatitis
NK cells and γδ+ T cells are phenotypically and functionally defective due to preferential apoptosis in patients with atopic dermatitis
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DOI：
10.4049/jimmunol.176.12.7736
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发表时间：
2006-06-15
影响因子：
4.4
通讯作者：
Shiohara, Tetsuo
中科院分区：
文献类型：
--
作者：
Katsuta, Michie;Takigawa, Yukio;Shiohara, Tetsuo
先天性免疫细胞介导抵抗病原体的第一道防线，并主要通过产生大量细胞因子来决定随后的获得性免疫应答的性质。鉴于这些不同的任务，可以预测，缺陷的NK和γ δ（+）T细胞反应可能是在特应性皮炎（AD）中观察到的免疫学改变的潜在机制。事实上，AD患者循环NK细胞和γ δ（+）T细胞的频率显著降低。它们还显示出在体外刺激后维持TNF-α和IFN-γ而不是IL-4产生的缺陷能力，并且该缺陷仅限于先天免疫细胞。令人惊讶的是，在CD 14（+）单核细胞耗竭时，TNF-α和IFN-γ产生的这种选择性损伤恢复到与对照中观察到的水平相当。单核细胞释放IL-10不是NK和γ δ（+）T细胞功能障碍的主要机制。当在单核细胞存在下刺激时，在AD患者的NK和γ δ（+）T细胞中优先观察到如通过膜联蛋白V结合所揭示的细胞凋亡，并且单核细胞的耗竭显著保护这些细胞免于凋亡性细胞死亡。AD患者活化的单核细胞对NK细胞的优先凋亡具有细胞接触依赖性。这些结果表明，一旦AD患者中的NK和γ δ（+）T细胞与活化的单核细胞直接接触，这些细胞特异性地靶向凋亡，导致1型细胞因子产生减少，从而将随后的获得性免疫应答导向2型模式并增加对感染的易感性。
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 gamma delta(+) 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 gamma delta(+) 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 gamma delta(+) T cell dysfunction. Apoptosis as revealed by annexin V binding, was preferentially observed in NK and gamma delta(+) 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 gamma delta(+) 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.