Group 2 innate lymphoid cells (ILC2s) are innate effectors playing an important role in the defense against helminthic infections and in the pathogenesis of allergic inflammation. Cytokines have been identified as the major stimuli driving ILC2 activation and expansion. Conversely, it is unclear whether costimulatory molecules contribute to regulation of ILC2 functions. ILC2s display high expression of inducible T-cell costimulator (ICOS), which belongs to the CD28 superfamily, and which has been shown to control late effector T-cell functions, and is of utmost importance for the humoral immune response. However, the biological function of ICOS expression on ILC2s is unknown. Here, we show that ICOS signaling in mice regulates ILC2 homeostasis independently of T cells and B cells, by promoting proliferation and accumulation of mature ILC2s in lung and intestine. In a model of IL-33-induced airway inflammation, ICOS controls ILC2 activation and eosinophil infiltration in the lung. Our data identify a role of ICOS in innate immunity and indicate that not only cytokines, but also costimulatory pathways such as those involving ICOS, can contribute to regulate the ILC2 pool. Thus, ICOS costimulation blockade, which is currently under clinical evaluation for inhibiting the humoral immune response, could also target innate inflammatory circuits. Originally, ICOS was considered to be an exclusive T-cell specific activation molecule. However, in 2010 [6] ILC2s were identified as a second cell type expressing high levels of ICOS. So far, ICOS function in ILC2s has not been investigated. In this study, we aimed to analyze the role of ICOS signaling in regulating phenotype, cytokine production, and proliferation of ILC2s and demonstrated that this pathway contributes substantially to regulate ILC2 expansion under homeostatic as well as under inflammatory conditions in vivo.
Results and discussion
Numbers of KLRG1+ ILC2s are diminished in the absence of ICOS signaling ICOS expression was analyzed on ILC2s and ILC3s, as gated in Supporting Information Fig. 1A. ICOS was highly expressed on ILC2s and to a lower extent also on ILC3s (Fig. 1A), as previously shown [6,20]. Conversely, ILC2s and ILC3s lacked the costimulator CD28 (Supporting Information Fig. 1B), demonstrating that ICOS expression on ILC2s is not dependent on CD28 costimulation, in contrast to what has been shown for T cells [21]. In line with these findings, ICOS expression on ILC2s and ILC3s was similar in CD28 −/− mice compared to WT mice (Fig. 1A). Next, we analyzed whether ILC2 and ILC3 numbers are influenced by the lack of ICOS signaling. ILC2s were significantly decreased in lung of ICOS ligand (ICOSL −/− ) and of ICOS −/− mice (Fig. 1B), while no difference was observed in CD28 −/− mice (Supporting Information Fig. 1C). A similar reduction in ILC2s could be observed in the small intestine (Si) lamina propria (LP) of both ICOSL −/− and of ICOS −/− mice (Fig. 1C). In contrast, ILC3 numbers were completely unchanged (Supporting Information Fig. 1D). By analyzi...
