Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Curr Opin Immunol. 2019 Feb;56:76-81. doi: 10.1016/j.coi.2018.11.001. Epub 2018 Nov 23.
A cardinal feature of the T-cell adaptive immune system is the antigen-dependent activation of naïve T cells in secondary lymphoid sites, followed by the migration of the resultant effector cells through the efferent lymph to the blood and then into a peripheral tissue site of infection or tumor growth. In contrast, the current view of innate lymphocytes (ILCs), the innate counterparts of T cells, is that they are tissue-resident cells, adapted to their specific environments during development and performing their effector functions locally upon cytokine stimulation. Here we present recent findings that challenge the latter as defining the properties of ILCs, at least ILC2s. Our studies show that IL-25, administrated experimentally or generated in response to helminth infection, triggers local proliferation and activation of intestinal ILC2s that are the precursors to inflammatory ILC2 (iILC2) cells. These cells downregulate CD69 expression, upregulate S1P receptors and move across the villus lymphatic endothelium in an S1P-depndent manner. They subsequently enter the blood stream, through which they traffic to distant organs such as the liver and lung. In the lung, these iILC2 cells play a crucial role in host defense during the pulmonary stage of helminth infection. In the later stage of infection, a fraction of the iILC2 cells phenotypically convert into lung-resident natural ILC2 (nILC2)-like cells while another fraction homes back to their original location in the small intestine. These data support the view that ILC2s possess properties considered characteristic of adaptive T lymphocytes, namely local activation and distant effector function, but in response to alarm cytokines instead of specific antigen. These findings also raise questions about whether other ILC subsets show similar trafficking potential when suitably challenged, the extent to which such cells show plasticity in adapting to new tissue environments beyond the course of early development, and the relative roles of organ-resident versus migratory ILCs in host defense.
T 细胞适应性免疫系统的一个主要特征是，在次级淋巴组织中，抗原依赖性激活初始 T 细胞，随后效应细胞通过输出淋巴管进入血液，然后进入感染或肿瘤生长的外周组织部位。相比之下，目前对先天淋巴细胞（ILC）的看法是，它们是组织驻留细胞，在发育过程中适应其特定环境，并在受到细胞因子刺激时在局部发挥效应功能。在这里，我们提出了一些新的发现，这些发现挑战了上述观点，至少对 ILC2 是如此。我们的研究表明，IL-25 无论是实验性给药还是对寄生虫感染的反应产生，都会触发肠道 ILC2 的局部增殖和激活，而 ILC2 是炎症性 ILC2（iILC2）细胞的前体。这些细胞下调 CD69 的表达，上调 S1P 受体，并以 S1P 依赖的方式穿过绒毛淋巴管内皮细胞。随后，它们通过血流迁移到远离器官，如肝脏和肺部。在肺部，这些 iILC2 细胞在寄生虫感染的肺部阶段对宿主防御起着至关重要的作用。在感染的后期阶段，一部分 iILC2 细胞表型转化为肺驻留的天然 ILC2（nILC2）样细胞，而另一部分则回到它们在小肠中的原始位置。这些数据支持这样一种观点，即 ILC2 具有被认为是适应性 T 淋巴细胞所特有的特性，即局部激活和远处效应功能，但对警报细胞因子而不是特定抗原作出反应。这些发现还提出了一些问题，即其他 ILC 亚群在受到适当挑战时是否表现出类似的迁移潜力，以及这些细胞在适应早期发育以外的新组织环境时表现出多大的可塑性，以及器官驻留细胞和迁移性 ILC 在宿主防御中的相对作用。
