Goverse Gera, Labao-Almeida Carlos, Ferreira Manuela, Molenaar Rosalie, Wahlen Sigrid, Konijn Tanja, Koning Jasper, Veiga-Fernandes Henrique, Mebius Reina E
Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 BT Amsterdam, the Netherlands; and.
Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, 1649-028 Lisbon, Portugal.
J Immunol. 2016 Jun 15;196(12):5148-55. doi: 10.4049/jimmunol.1501106. Epub 2016 May 9.
Changes in diet and microbiota have determining effects on the function of the mucosal immune system. For example, the active metabolite of vitamin A, retinoic acid (RA), has been described to maintain homeostasis in the intestine by its influence on both lymphocytes and myeloid cells. Additionally, innate lymphoid cells (ILCs), important producers of cytokines necessary for intestinal homeostasis, are also influenced by vitamin A in the small intestines. In this study, we show a reduction of both NCR(-) and NCR(+) ILC3 subsets in the small intestine of mice raised on a vitamin A-deficient diet. Additionally, the percentages of IL-22-producing ILCs were reduced in the absence of dietary vitamin A. Conversely, mice receiving additional RA had a specific increase in the NCR(-) ILC3 subset, which contains the lymphoid tissue inducer cells. The dependence of lymphoid tissue inducer cells on vitamin A was furthermore illustrated by impaired development of enteric lymphoid tissues in vitamin A-deficient mice. These effects were a direct consequence of ILC-intrinsic RA signaling, because retinoic acid-related orphan receptor γt-Cre × RARα-DN mice had reduced numbers of NCR(-) and NCR(+) ILC3 subsets within the small intestine. However, lymphoid tissue inducer cells were not affected in these mice nor was the formation of enteric lymphoid tissue, demonstrating that the onset of RA signaling might take place before retinoic acid-related orphan receptor γt is expressed on lymphoid tissue inducer cells. Taken together, our data show an important role for vitamin A in controlling innate lymphoid cells and, consequently, postnatal formed lymphoid tissues within the small intestines.
饮食和微生物群的变化对黏膜免疫系统的功能具有决定性影响。例如，维生素A的活性代谢产物视黄酸（RA）已被描述为通过对淋巴细胞和髓样细胞的影响来维持肠道内稳态。此外，固有淋巴细胞（ILC）是肠道内稳态所需细胞因子的重要产生者，在小肠中也受维生素A的影响。在本研究中，我们发现以维生素A缺乏饮食饲养的小鼠小肠中NCR(-)和NCR(+) ILC3亚群均减少。此外，在缺乏膳食维生素A的情况下，产生IL-22的ILC百分比降低。相反，接受额外RA的小鼠NCR(-) ILC3亚群有特异性增加，该亚群包含淋巴组织诱导细胞。维生素A缺乏小鼠肠道淋巴组织发育受损进一步说明了淋巴组织诱导细胞对维生素A的依赖性。这些效应是ILC内在RA信号传导的直接结果，因为视黄酸相关孤儿受体γt-Cre×RARα-DN小鼠小肠内NCR(-)和NCR(+) ILC3亚群数量减少。然而，这些小鼠中的淋巴组织诱导细胞未受影响，肠道淋巴组织的形成也未受影响，这表明RA信号传导的起始可能在视黄酸相关孤儿受体γt在淋巴组织诱导细胞上表达之前发生。综上所述，我们的数据表明维生素A在控制固有淋巴细胞以及因此在小肠内出生后形成的淋巴组织方面发挥重要作用。
