Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674, USA.
Immunity. 2013 Mar 21;38(3):514-27. doi: 10.1016/j.immuni.2013.02.011. Epub 2013 Feb 28.
Interleukin-21 (IL-21) has broad actions on T and B cells, but its actions in innate immunity are poorly understood. Here we show that IL-21 induced apoptosis of conventional dendritic cells (cDCs) via STAT3 and Bim, and this was inhibited by granulocyte-macrophage colony-stimulating factor (GM-CSF). ChIP-Seq analysis revealed genome-wide binding competition between GM-CSF-induced STAT5 and IL-21-induced STAT3. Expression of IL-21 in vivo decreased cDC numbers, and this was prevented by GM-CSF. Moreover, repetitive α-galactosylceramide injection of mice induced IL-21 but decreased GM-CSF production by natural killer T (NKT) cells, correlating with decreased cDC numbers. Furthermore, adoptive transfer of wild-type CD4+ T cells caused more severe colitis with increased DCs and interferon-γ (IFN-γ)-producing CD4+ T cells in Il21r(-/-)Rag2(-/-) mice (which lack T cells and have IL-21-unresponsive DCs) than in Rag2(-/-) mice. Thus, IL-21 and GM-CSF exhibit cross-regulatory actions on gene regulation and apoptosis, regulating cDC numbers and thereby the magnitude of the immune response.
白细胞介素-21（IL-21）对 T 和 B 细胞有广泛的作用，但它在先天免疫中的作用还不太清楚。在这里，我们表明，IL-21 通过 STAT3 和 Bim 诱导常规树突状细胞（cDC）凋亡，而粒细胞-巨噬细胞集落刺激因子（GM-CSF）则抑制了这种作用。ChIP-Seq 分析显示，GM-CSF 诱导的 STAT5 和 IL-21 诱导的 STAT3 之间存在全基因组结合竞争。体内表达 IL-21 会减少 cDC 的数量，而 GM-CSF 则可以预防这种情况。此外，重复注射α-半乳糖神经酰胺会诱导 IL-21 的产生，但会减少自然杀伤 T（NKT）细胞产生 GM-CSF，这与 cDC 数量的减少有关。此外，野生型 CD4+T 细胞的过继转移会导致 Il21r(-/-)Rag2(-/-)小鼠（缺乏 T 细胞且具有对 IL-21 无反应的 DC）比 Rag2(-/-)小鼠更严重的结肠炎，导致 DC 和产生干扰素-γ（IFN-γ）的 CD4+T 细胞增加。因此，IL-21 和 GM-CSF 在基因调控和凋亡方面表现出交叉调节作用，调节 cDC 的数量，从而调节免疫反应的强度。
