IL-33 and the PKA Pathway Regulate ILC2 Populations Expressing IL-9 and ST2

Abstract

Type 2 Innate lymphoid cells (ILC2s) are tissue-resident immune cells activated by epithelial-derived alarmins upon tissue damage. They regulate immunity against helminth parasites and allergies by expressing type 2 immune response cytokines including IL-9, known to be critical for inducing and potentiating the immune response in such context. Although ILC2s are reported to be the main source of IL-9 in mice during N. brasiliensis infection, the mechanisms that regulate the expression of IL-9 in these cells are yet to be described. Recent studies have shown that in addition to cytokines, multiple molecules can differentially modulate the functions of ILC2s in various contexts both in vitro and in vivo. Among these stimuli are lipid mediators and neuropeptides, which activate the PKA pathway and have been associated with the regulation of type 2 immune cytokines. In this work we found that ILC2s in mice infected with N. brasiliensis can be classified into different groups based on the expression of IL-9 and ST2. These distinct populations were distributed in the lung and the small intestine. Through the development of an in vitro culture system, we sought to determine the stimuli that regulate the expression of these markers in ILC2s. We identified the alarmin IL-33 as being a key player for increased IL-9 expression. Additionally, we found the PKA pathway to be a dual regulator of ILC2 cells, working synergistically with IL-33 to enhance IL-9 production and capable of modulating proliferation and the expression of ILC2 markers. These data provide further evidence of a high heterogeneity between ILC2 subsets in a context dependent manner and calls for careful consideration when choosing the markers to identify these cells in vivo. Distinguishing ILC2 subsets and dissecting their mechanisms of activation is critical for a deeper understanding of the biology of these cells, allowing their manipulation for therapeutic purposes.

Transcriptional control of ILC identity

“…In contrast to iILC2s, nILC2s are tissue-resident cells that produce more IL-9 after activation ( 152 ). IL-33 and TSLP activate IL-9 production by ILC2s which further induces IL-5 and IL-13 during helminth infection ( 41 , 42 , 154 ). Since ILC2s express IL-9R, ILC2-derived IL-5/IL-13 can be regulated in autocrine manner by IL-9 ( 41 , 154 ).…”

“…IL-33 and TSLP activate IL-9 production by ILC2s which further induces IL-5 and IL-13 during helminth infection ( 41 , 42 , 154 ). Since ILC2s express IL-9R, ILC2-derived IL-5/IL-13 can be regulated in autocrine manner by IL-9 ( 41 , 154 ). Similar to T cells, IL-9 production in ILC2s depends on the transcription factor IRF4 ( 42 , 155 ).…”

CAVO Inhibits Airway Inflammation and ILC2s in OVA‐Induced Murine Asthma Mice

“…ST2 is a component of the IL-33 receptor and can help IL-33 to exert its function, which is commonly used as a marker for ILC2s identification. KLRG1 can induce ILC2s proliferation and IL13 production [13,14]. Recent asthma studies have indicated that ILC2s initiate and enhance allergic airway inflammation and steroid resistance [15][16][17].…”