Abstract
Group-2 innate lymphoid cells (ILC2) play critical roles in the initiation and maintenance of type-2 immune responses, predominantly through their production of the type-2 cytokines IL-5, IL-9, and IL-13. ILC2 are essential for the efficient elimination of helminth parasites, but also contribute to the detrimental type-2 immune responses that underlie diseases such as asthma and allergy. While several transcription factors have been identified that regulate the development and function of ILC2, less is known about the post-transcriptional mechanisms that regulate these processes. We identified micro-RNAs (miRNAs) that are co-ordinately regulated in ILC2 from mice exposed to two different stimuli, namely IL-33 “alarmin” administration or Nippostrongylus brasiliensis parasitic worm infection. miR-155 is upregulated in ILC2 in response to both stimuli and miR-155−/− mice had impaired IL-33-driven ILC2 responses. Using mixed bone marrow chimeras, we demonstrate that this deficit is intrinsic to ILC2 and that miR-155 protects ILC2 from apoptosis, while having little impact on ILC2 proliferation or cytokine production. These data reveal a subset of miRNAs that are regulated upon ILC2 activation and establish a specific role for miR-155 in regulating ILC2 survival following activation.
Highlights
Group-2 innate lymphoid cells (ILC2) are tissue-resident immune cells that represent a significant early source of the type-2 cytokines IL-5, IL-9, and IL-13 and play important roles in the initiation and maintenance of type-2 immune responses
To determine the expression of miRNAs in ILC2 following activation, we isolated ILC2 (CD3−CD4−Lineage−ICOS+) from the abdominal lymph nodes of naïve wildtype (WT) mice or WT mice treated with IL-33 or infected with N. brasiliensis. miRNA expression profiles were established using microarray and confirmatory PCR (IL-33 data only, data not shown)
MiR-155 was selected for further study as it ranked highly in fold-change (18.9-fold increase) in IL-33-treated mice and has been implicated previously in lymphocyte development and Th2 cell immunity. miRNA differentially expressed between naïve ILC2 and ILC2 following in vivo IL33-stimulation or N. brasiliensis-infection, and T cells upon N. brasiliensisinfection indicated considerable co-incidence of miRNA modulation (Figure 1C and Supplementary Tables 1–7)
Summary
Group-2 innate lymphoid cells (ILC2) are tissue-resident immune cells that represent a significant early source of the type-2 cytokines IL-5, IL-9, and IL-13 and play important roles in the initiation and maintenance of type-2 immune responses. ILC2 play critical roles in the elimination of helminth parasites [1], and in the etiology of allergic diseases such as eczema [2] and asthma [3,4,5]. ILC2 originate from common lymphoid progenitors (CLP) and several key transcription factors have been identified that regulate their development and function [11]. Development of all ILCs miR-155 Protects ILC2s From Apoptosis requires the combined actions of several key factors, including Id2, Gata, PLZF, and TCF-1 [12]. Lineage-specific factors, such as RORα, Bcl11b, and high levels of Gata, are subsequently required to specify the ILC2 lineage
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