ILC2s — resident lymphocytes pre-adapted to a specific tissue or migratory effectors that adapt to where they move?

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.