Research ArticleImmunology

Notch signaling in group 3 innate lymphoid cells modulates their plasticity

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Science Signaling  03 May 2016:
Vol. 9, Issue 426, pp. ra45
DOI: 10.1126/scisignal.aaf2223

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Plasticity in innate lymphoid cell function

Like the T cells and B cells of the adaptive immune system, cells in the innate immune system are key to organismal health. Innate lymphoid cells (ILCs) are a heterogeneous type of innate immune cell that regulates immune responses and tolerance at mucosal surfaces, such as in the gut, by rapidly secreting cytokines. Group 3 ILCs (ILC3s) are characterized by the presence or absence of a cell surface natural cytotoxicity receptor (NCR). Two studies now provide evidence of heterogeneity and plasticity within ILC3s. Chea et al. found that a substantial proportion of mouse NCR ILC3s differentiated into NCR+ ILC3s in response to stimulation of the receptor Notch2. In mice with defective Notch signaling specifically in lymphoid cells, NCR+ ILC3s were reduced in number and showed impaired cytokine secretion. Viant et al. showed that Notch signaling was required for the maintenance of NCR+ ILC3s. Furthermore, signaling by the cytokine transforming growth factor–β (TGF-β) antagonized Notch signaling, resulting in reduced numbers of NCR+ ILC3s. Together, these studies indicate that ILC3 subset composition in vivo depends on the balance between different signals found in tissue microenvironments, which has implications for whether proinflammatory immune responses or immune tolerance will prevail.


The Notch signaling pathway is conserved throughout evolution, and it controls various processes, including cell fate determination, differentiation, and proliferation. Innate lymphoid cells (ILCs) are lymphoid cells lacking antigen receptors that fulfill effector and regulatory functions in innate immunity and tissue remodeling. Type 3 ILCs (ILC3s) reinforce the epithelial barrier and maintain homeostasis with intestinal microbiota. We demonstrated that the population of natural cytotoxicity receptor–positive (NCR+) ILC3s in mice is composed of two subsets that have distinct developmental requirements. A major subset depended on the activation of Notch2 in NCR ILC3 precursors in the lamina propria of the small intestine to stimulate expression of the genes encoding the transcription factors T-bet, RORγt, and aryl hydrocarbon receptor (AhR). Notch signaling contributed to the transition of NCR cells into NCR+ cells, the more proinflammatory subset, in a cell-autonomous manner. In the absence of Notch signaling, this subset of NCR ILC3s did not acquire the gene expression profile of NCR+ ILC3s. A second subset of NCR+ ILC3s did not depend on Notch for their development or for increased transcription factor abundance; however, their production of cytokines and cell surface abundance of NCRs were decreased in the absence of Notch signaling. Together, our data suggest that Notch is a regulator of the plasticity of ILC3s by controlling NCR+ cell fate.

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