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

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.

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

“…This is supported by cell fate mapping experiments that suggest that instability of NKp46 expression in ILC3s found in the intestine reflects a major role of this receptor in tuning the very dynamic environmental signals encountered that drive ILC3 plasticity. 45,46 Loss of Ncr1 has previously been shown not to affect ILC3 development with Ncr1 gfp/gfp Rag2 −/- mice showing survival and clinical scores similar to control mice when challenged with the enteric infection Citrobacter rodentium . 47 In this setting, NKp46 expression did not appear to be essential for protection.…”

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…Fate‐mapping of the NKp46 locus revealed populations of ‘ex‐NKp46 ILC3’ that no longer expressed NKp46, many of which had reverted to a ‘double‐negative’ ILC3 phenotype 74, 75. Transition between phenotypes was regulated locally via Notch and suppressed by transforming growth factor‐ β , suggesting that the NKp46 + ILC3 phenotype is unstable and dynamically regulated 74, 75.…”

“…Fate‐mapping of the NKp46 locus revealed populations of ‘ex‐NKp46 ILC3’ that no longer expressed NKp46, many of which had reverted to a ‘double‐negative’ ILC3 phenotype 74, 75. Transition between phenotypes was regulated locally via Notch and suppressed by transforming growth factor‐ β , suggesting that the NKp46 + ILC3 phenotype is unstable and dynamically regulated 74, 75. Surprisingly, a small proportion of CD4 − CCR6 + ILC3 also exhibited a history of NKp46 expression, suggesting that at least some ILC3 with an LTi‐like phenotype may be derived from the same precursor as NKp46 + ILC3, rather than from a pure LTi‐precursor 74.…”

Les cellules lymphoïdes innées

“…In vitro, des ILC3 NCR -de souris peuvent se différencier en ILC3 NCR + , et inversement. La voie de signalisation Notch qui a un rôle important dans le développement d'une partie des ILC3 [21], induit, in vitro, la transformation des ILC3 NCR -en ILC3 NCR + [22]. 1 Le DSS est couramment utilisé comme modèle de colites inflammatoires aiguës.…”

“…Les ILC auxiliaires auraient une longue demi-vie et seraient reconstituées par auto-renouvellement ou par des précur-seurs périphériques résidant au sein du tissu [15]. Cette hypothèse est supportée par l'observation de l'implication, À l'inverse, le TGF- (transforming growth factor-beta) inhibe cette voie de différenciation des ILC3 NCR -en ILC3 NCR + [22]. Les ILC qui sont considérées comme des cellules différenciées peuvent donc, sous l'influence de facteurs extérieurs, modifier de façon importante leur programme de transcription génique, leur profil d'expression de molécules de surface et de cytokines.…”