2. THE INNATE LYMPHOID CELLS (ILC)
To maintain tissue homeostasis and integrity, lungs are protected by a complex network of highly specialized immune cells that include ILC [10,11]. Creating a first-line defense system, these cells play diverse roles in inflammation and infection, including promotion of innate immunity, acquisition of adaptive immunity, maintenance of epithelial barrier function and tissue repair [9-11,19]. Being tissue-resident elements, ILC tend to proliferate locally following environmental challenges [9-11,18]. However, there is increasing evidence that, in inflammatory disorders, ILC migrating from other organs could contribute to the expansion and the modulation of the local cell pools [19-21]. Based on distinctive phenotypic markers, transcription factors and effector function, ILC can be divided into three subsets: ILC1, ILC2 and ILC3. These ILC subsets share many phenotypic, morphological, and functional features with CD4+ Th1, Th2 and Th17 cells [9,10,18-21]. However, in contrast with T-cells, regulated by antigen presentation via antigen-presenting cells, ILC are mainly regulated by soluble factors such as cytokines, chemokines, neuronal factors, and other inflammatory mediators [22-25]. ILC1 express the transcription factor Tbx21 and, in response to IL-12, IL-15, and IL-18, produce IFN-γ and TNF-α (figure 1A). ILC2 express the transcription factor GATA-3 and, in response to the alarmins TSLP, IL-25, HMGB1 and IL-33, secrete the classical type 2 effector cytokines IL-4, IL-5 and IL-13 [26]. ILC3 express the transcription factor RORγt and, in response to IL-23 and IL-1β, release IL-17 and IL-22 [20,27]. ILC subsets are not ‘fixed’ and exhibit considerable functional plasticity depending on the inflammatory milieu [28]. For example, ILC2 can transdifferentiate into ILC1 or ILC3 in response to IL-1β, IL-12 and TGF-β but this switch is bi-directional, as these transdifferentiations can be reversed by IL-4 (figure 1B) [28]. Additionally, TLR-2 activation can promote the production of the Th2 cytokines IL-5 and IL-13 by ILC3, which suggests that these cells might be able to differentiate into ILC2 (figure 1C) [29]. Finally early reports suggest that ILC2 are significantly more potent than Th2 cells, producing greater than 10-fold the amount of Th2 cytokines on a per-cell basis [30], explaining why ILC2 may have a significant role in several inflammatory disorders and, possibly, in reduced response to corticosteroids. Increased proportions of sputum and blood ILC2 were detected in children with severe therapy-resistant asthma [8]. In these children ILC2s were significantly reducedin vitro when cultured with steroids and in vivo following intramuscular triamcinolone. Systemic corticosteroids, but not maintenance inhaled steroids, resulted in improved symptom control and exacerbations [8]