Interferon-γ Receptor Signaling in Dendritic Cells Restrains Spontaneous Proliferation of CD4+ T Cells in Chronic Lymphopenic Mice
Interferon-γ Receptor Signaling in Dendritic Cells Restrains Spontaneous Proliferation of CD4+ T Cells in Chronic Lymphopenic Mice
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DOI：
10.3389/fimmu.2019.00140
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发表时间：
2019-02-07
影响因子：
7.3
通讯作者：
Schueler, Thomas
中科院分区：
文献类型：
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作者：
Knop, Laura;Frommer, Charlotte;Schueler, Thomas
在淋巴细胞减少的小鼠中，T细胞被激活并经历淋巴细胞减少诱导的增殖（LIP）。然而，并非所有的T细胞对淋巴细胞减少症都同样敏感。描述了几种淋巴细胞减少不敏感的T细胞克隆，它们的非反应性主要归因于克隆特异性。在这里，我们提供了一个额外的，宿主依赖性机制抑制LIP淋巴细胞减少不敏感的CD 4（+）T细胞的证据。我们表明，这些细胞在缺乏IFN-γ受体（IFN-γ R）表达的淋巴细胞减少小鼠中经历LIP，这是一个由T细胞衍生的IFN-γ的自分泌作用促进的过程。此外，淋巴细胞减少不敏感的CD 4（+）T细胞的LIP需要完整的微生物群落，并伴随着IL-6和树突状细胞（DC）的大量积累。与这些结果一致，IL-6中和和IFN-γ R表达的DC特异性恢复都足以限制LIP。因此，CD 4（+）T细胞对淋巴细胞减少症的不敏感性依赖于细胞内在特性和肠道微生物菌群、IL-6、IFN-γ R+ DC和T细胞衍生的IFN-γ之间的复杂相互作用。
In lymphopenic mice, T cells become activated and undergo lymphopenia-induced proliferation (LIP). However, not all T cells are equally sensitive to lymphopenia. Several lymphopenia-insensitive T cell clones were described and their non-responsiveness was mainly attributed to clone-specific properties. Here, we provide evidence for an additional, host-dependent mechanism restraining LIP of lymphopenia-insensitive CD4(+) T cells. We show that such cells undergo LIP in lymphopenic mice lacking IFN-gamma receptor (IFN-gamma R) expression, a process, which is promoted by the autocrine action of T cell-derived IFN-gamma. Additionally, LIP of lymphopenia-insensitive CD4(+) T cells requires an intact microflora and is accompanied by the massive accumulation of IL-6 and dendritic cells (DCs). Consistent with these results, IL-6 neutralization and the DC-specific restoration of IFN-gamma R expression are both sufficient to restrict LIP. Hence, the insensitivity of CD4(+) T cells to lymphopenia relies on cell-intrinsic properties and a complex interplay between the commensal microflora, IL-6, IFN-gamma R+ DCs, and T cell-derived IFN-gamma.