Research ArticleImmunology

Transforming growth factor–β and Notch ligands act as opposing environmental cues in regulating the plasticity of type 3 innate lymphoid cells

Sci. Signal.  03 May 2016:
Vol. 9, Issue 426, pp. ra46
DOI: 10.1126/scisignal.aaf2176

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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 immune responses or tolerance will prevail.

Abstract

Group 3 innate lymphoid cells (ILC3s) are composed of subsets that are either positive or negative for the natural cytotoxicity receptor (NCR) NKp46 (encoded by Ncr1). ILC3s are located at mucosal sites, such as in the intestine and lung, where they are exposed to billions of commensal microbes and potentially harmful pathogens. Together with T cells, the various ILC3 subsets maintain the balance between homeostasis and immune activation. Through genetic mapping, we identified a previously uncharacterized subset of NCR ILC3s in mice that transiently express Ncr1, demonstrating previously undescribed heterogeneity within the ILC3 population. In addition, we showed that sustained Notch signaling was required for the maintenance of the NCR+ phenotype and that the cytokine transforming growth factor–β (TGF-β) impaired the development of NCR+ ILC3s. Thus, the plasticity of ILC3s is regulated by the balance between the opposing effects of Notch and TGF-β signaling, maintaining homeostasis in the face of continual challenges.

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