In this study, we have evaluated the therapeutic effect of an IL-15 / sIL-15Rα complex on pulmonary inflammation and in particular through a mouse model of acute HDM allergic asthma. We found that the IL-15Cx can modulate lung inflammation but has no effect on asthma features in mouse. Indeed, focusing on the three main physiopathological pillars of asthma, our results show that the IL-15Cx did not decrease bronchial hyperreactivity, did not reduce bronchial remodeling or cellular bronchial infiltrate, but reduced bronchial mucus secretion and modulated systemic inflammatory response. Using ovalbumin sensitized transgenic mice with an increased number of memory-like CD8
+ T cells in peripheral lymphoid tissues, Th2-type cytokine production was found to be severely attenuated after inhalation of ovalbumin. Transgenic mice overexpressing IL-15 preferentially developed CD8
+ T cell-mediated Th1 responses after ovalbumin sensitization [
17]. Mathias et al. have made it possible to better characterize the role of this cytokine in the inflammatory response during the development of an allergic airway disease by using interleukin-15 deficient mice [
18]. They used wild-type and IL-15 deficient mice that were sensitized and then exposed to ovalbumin. In the absence of IL-15, ovalbumin-sensitive mice exhibited increased bronchial eosinophil inflammation, high IL-13 production, and severe pulmonary histopathology damages compared to wild type mice. These results clearly demonstrate that mice with endogenous IL-15 deficiency are likely to develop a strong, potent and Th2-mediated allergic airway disease, which could be regulated by CD8
+ T cells. Recently it has been shown that IL-15 deficiency increases airway resistance and decreases compliance in a mouse model of asthma [
14]. These discrepancies with our observation might be linked to several points. First, we used a lower dose of IL-15 than others. Therefore, an insufficient dose injected could explain the absence of an effect on bronchial hyperreactivity. It is of note that the dose we used demonstrated a biological effect stronger than IL-15 alone [
19]. Secondly, we used a mouse model of asthma induced by HDM mimicking the human situation in a more complex manner than the airway inflammation induced by ovalbumin. In fact, our model displays a mix Th2/Th17 inflammation associated with a mix eosinophil/neutrophil infiltrate. Therefore, it is likely that in our model, mechanisms implicated might be more complicated, yet closer to the human situation, and several compensatory effects may explain our observation. Despite the potential effect of IL-15Cx on Th2 inflammation, we did not use it on an ovalbumin-induced asthma model, a pure Th2 model. Indeed, if the development of new therapies in asthma remains essential, the last years have seen the emergence of biotherapies efficiently targeting the Th2 pathway (anti-IL5, anti-RIL-5) in severe asthma [
20,
21]. Research must therefore now focus on patients with a part of non-Th2 inflammation in which oral corticosteroids is often the only option, with unacceptable side effects. We therefore went directly on a mouse model with a mixed Th2 and non-Th2 inflammation, which has already proven itself [
15]. After the study of bronchial hyperreactivity we were interested in the action of the complex on bronchial remodeling and cellular infiltrate. The complex does not seem to interfere with bronchial remodeling. Nevertheless, the analysis of the secretion of mucus by bronchial goblet cells through the use of a score after PAS staining, found a significant decrease thereof. The mechanism of action explaining this effect remains to be elucidated by studying the components of the IL-15 receptor present on the goblet cells of asthmatic subjects. With respect to inflammatory modulation, we observed that in control mice, injection of the IL-15 / sIL-15Rα complex had systemic and a local effect on NK cells. In addition, we observed an increase in CD8
+ memory and T regulatory lymphocytes. NK cells have an immunoregulatory role in many inflammatory pathologies and their involvement in asthma remains highly controversial in the literature. The development of house dust mite allergic asthma in mice has been shown to increase NK, particularly in the mediastinal lymph nodes, but NK blockade by antibodies or their genetic deficiency does not alter the characteristics of asthma, namely Th2 inflammation, bronchial hyperreactivity, specific IgE titers, and mucus production [
22]. The study of the prostaglandin I2 receptor deficiency in a HDM allergic murine model shows an increase in IFN-γ producing NK cells in the lungs, inversely correlated with the number of type 2 innate lymphoid cells (ILC2). In addition, anti-NK-1.1 monoclonal antibody treatment restored inflammation of the allergic airways and increased the level of IL-5 producing, attracting eosinophils. This study thus reveals that NK cells prevent allergic pulmonary inflammation by limiting the number of ILC2 [
23]. Furthermore, the mode of administration of the complex can influence the biological activity and explain our results showing a difference in the spleen (systemic) and not at the tissue level. In this context, the administration of the complex by aerosol would be an interesting track. Finally, viral exacerbations are the leading cause of exacerbation of asthma in winter, and an increase in memory T8 lymphocytes would perhaps reduce these exacerbations in targeted populations. Indeed, Laza-Stanca et al demonstrated that IL-15 deficiency in humans could be a part of the virus-induced asthma exacerbations pathogenesis [
24]. In asthma, Th1 and Treg populations are not directly involved in the allergic reaction but are rather involved as antagonists and regulators [
25]. Th1 population, secreting interferon gamma (IFNγ), will modulate the allergic reaction by limiting the expansion of the Th2 population and inducing cell-mediated immunity [
26]. The other regulatory T cell population, via the secretion of IL-10 and tumor growth factor beta (TGF-β), will inhibit the Th1, Th2 and Th17 responses to restore the pro-inflammatory/anti-inflammatory balance [
27]. Tregs inactivate the inflammatory response in order to stop bronchial inflammation but are quantitatively and qualitatively deficient in this pathology [
28,
29]. In our model, the increase in Th1 CXCR3
+ in the Th1 pathway may also counteract the Th2 inflammation but these modulations do not seem to be sufficient. In the same way, a tendency to increase regulatory T cells in the lungs after injection of the complex is observed. Though we did not demonstrate a therapeutic effect of the IL-15Cx in our mouse model of house dust mite-allergic asthma, other therapies implicating IL-15 in asthma should not be completely abandoned. Indeed, it is clearly established that asthma syndrome recovers several different phenotypes with different endotypes, so that targeting one molecule could be relevant for one endotype but not for another. For instance, targeting IL-5 with mepolizumab on benralizumab is relevant for the eosinophilic phenotype whereas omalizumab concerns allergic asthma. IL-15 could be involved in another type of asthma for which our model, mainly Th2 and Th17-driven, is not relevant. Nevertheless, the modulation of inflammation induced by the IL-15 / sIL-15Rα complex is of major interest in inflammatory diseases such as psoriasis, transplantation or in oncology where the role of IL-15 is well established. Indeed, we demonstrated before that endogenous soluble IL-15Rα derived from epidermal stroma, protects against dendritic cell/IL-15-mediated, T cell-driven skin inflammation in vivo, and is relevant to human psoriasis [
30]. Regarding tolerance in lung transplantation,
Jungraithmayr et al. showed that expansion of recipient NK cells through IL-15/IL-15Rα complex treatment resulted in decreased T-cell infiltration and alloreactive T-cell priming as well as improved function of the allogeneic lung transplant in a mouse model [
31]. Other forms of the complex have been tested in oncology. A fusion protein called RLI, composed of the sushi domain of IL-15 receptor α coupled via a linker to IL-15, seems to have a high antitumor activity in metastatic melanoma and colorectal cancer in mice [
32]. ALT-803, is a new IL-15 superagonist composed of a mutant of human IL-15 and the sushi domain of human IL-15 Rα fused with the Fc domain IgG1. Recently, the use of ALT-803 in combination with NIVOLUMAB (anti-PD1) in non-small-cell metastatic lung cancers has been the subject of an encouraging Phase 1 study that has conducted to a Phase 2 study still in progress [
33]. A novel fusion protein encompassing anti-PD-L1 and the IL-15 superagonist fusion complex (ALT-803) called N-809 has been created and has very promising antitumor functionalities [
34]. The association of the complex with other existing targeted therapies could therefore also be an interesting research avenue
.